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Muscle – Wikipedia

Monday, December 19th, 2016

Muscle is a soft tissue found in most animals. Muscle cells contain protein filaments of actin and myosin that slide past one another, producing a contraction that changes both the length and the shape of the cell. Muscles function to produce force and motion. They are primarily responsible for maintaining and changing posture, locomotion, as well as movement of internal organs, such as the contraction of the heart and the movement of food through the digestive system via peristalsis.

Muscle tissues are derived from the mesodermal layer of embryonic germ cells in a process known as myogenesis. There are three types of muscle, skeletal or striated, cardiac, and smooth. Muscle action can be classified as being either voluntary or involuntary. Cardiac and smooth muscles contract without conscious thought and are termed involuntary, whereas the skeletal muscles contract upon command.[1] Skeletal muscles in turn can be divided into fast and slow twitch fibers.

Muscles are predominantly powered by the oxidation of fats and carbohydrates, but anaerobic chemical reactions are also used, particularly by fast twitch fibers. These chemical reactions produce adenosine triphosphate (ATP) molecules that are used to power the movement of the myosin heads.[2]

The term muscle is derived from the Latin musculus meaning "little mouse" perhaps because of the shape of certain muscles or because contracting muscles look like mice moving under the skin.[3][4]

The anatomy of muscles includes gross anatomy, which comprises all the muscles of an organism, and microanatomy, which comprises the structures of a single muscle.

Muscle tissue is a soft tissue, and is one of the four fundamental types of tissue present in animals. There are three types of muscle tissue recognized in vertebrates:

Cardiac and skeletal muscles are "striated" in that they contain sarcomeres that are packed into highly regular arrangements of bundles; the myofibrils of smooth muscle cells are not arranged in sarcomeres and so are not striated. While the sarcomeres in skeletal muscles are arranged in regular, parallel bundles, cardiac muscle sarcomeres connect at branching, irregular angles (called intercalated discs). Striated muscle contracts and relaxes in short, intense bursts, whereas smooth muscle sustains longer or even near-permanent contractions.

Skeletal (voluntary) muscle is further divided into two broad types: slow twitch and fast twitch:

The density of mammalian skeletal muscle tissue is about 1.06kg/liter.[8] This can be contrasted with the density of adipose tissue (fat), which is 0.9196kg/liter.[9] This makes muscle tissue approximately 15% denser than fat tissue.

All muscles are derived from paraxial mesoderm. The paraxial mesoderm is divided along the embryo's length into somites, corresponding to the segmentation of the body (most obviously seen in the vertebral column.[10] Each somite has 3 divisions, sclerotome (which forms vertebrae), dermatome (which forms skin), and myotome (which forms muscle). The myotome is divided into two sections, the epimere and hypomere, which form epaxial and hypaxial muscles, respectively. The only epaxial muscles in humans are the erector spinae and small intervertebral muscles, and are innervated by the dorsal rami of the spinal nerves. All other muscles, including those of the limbs are hypaxial, and inervated by the ventral rami of the spinal nerves.[10]

During development, myoblasts (muscle progenitor cells) either remain in the somite to form muscles associated with the vertebral column or migrate out into the body to form all other muscles. Myoblast migration is preceded by the formation of connective tissue frameworks, usually formed from the somatic lateral plate mesoderm. Myoblasts follow chemical signals to the appropriate locations, where they fuse into elongate skeletal muscle cells.[10]

Skeletal muscles are sheathed by a tough layer of connective tissue called the epimysium. The epimysium anchors muscle tissue to tendons at each end, where the epimysium becomes thicker and collagenous. It also protects muscles from friction against other muscles and bones. Within the epimysium are multiple bundles called fascicles, each of which contains 10 to 100 or more muscle fibers collectively sheathed by a perimysium. Besides surrounding each fascicle, the perimysium is a pathway for nerves and the flow of blood within the muscle. The threadlike muscle fibers are the individual muscle cells (myocytes), and each cell is encased within its own endomysium of collagen fibers. Thus, the overall muscle consists of fibers (cells) that are bundled into fascicles, which are themselves grouped together to form muscles. At each level of bundling, a collagenous membrane surrounds the bundle, and these membranes support muscle function both by resisting passive stretching of the tissue and by distributing forces applied to the muscle.[11] Scattered throughout the muscles are muscle spindles that provide sensory feedback information to the central nervous system. (This grouping structure is analogous to the organization of nerves which uses epineurium, perineurium, and endoneurium).

This same bundles-within-bundles structure is replicated within the muscle cells. Within the cells of the muscle are myofibrils, which themselves are bundles of protein filaments. The term "myofibril" should not be confused with "myofiber", which is a simply another name for a muscle cell. Myofibrils are complex strands of several kinds of protein filaments organized together into repeating units called sarcomeres. The striated appearance of both skeletal and cardiac muscle results from the regular pattern of sarcomeres within their cells. Although both of these types of muscle contain sarcomeres, the fibers in cardiac muscle are typically branched to form a network. Cardiac muscle fibers are interconnected by intercalated discs,[12] giving that tissue the appearance of a syncytium.

The filaments in a sarcomere are composed of actin and myosin.

The gross anatomy of a muscle is the most important indicator of its role in the body. There is an important distinction seen between pennate muscles and other muscles. In most muscles, all the fibers are oriented in the same direction, running in a line from the origin to the insertion. However, In pennate muscles, the individual fibers are oriented at an angle relative to the line of action, attaching to the origin and insertion tendons at each end. Because the contracting fibers are pulling at an angle to the overall action of the muscle, the change in length is smaller, but this same orientation allows for more fibers (thus more force) in a muscle of a given size. Pennate muscles are usually found where their length change is less important than maximum force, such as the rectus femoris.

Skeletal muscle is arranged in discrete muscles, an example of which is the biceps brachii (biceps). The tough, fibrous epimysium of skeletal muscle is both connected to and continuous with the tendons. In turn, the tendons connect to the periosteum layer surrounding the bones, permitting the transfer of force from the muscles to the skeleton. Together, these fibrous layers, along with tendons and ligaments, constitute the deep fascia of the body.

The muscular system consists of all the muscles present in a single body. There are approximately 650 skeletal muscles in the human body,[13] but an exact number is difficult to define. The difficulty lies partly in the fact that different sources group the muscles differently and partly in that some muscles, such as palmaris longus, are not always present.

A muscular slip is a narrow length of muscle that acts to augment a larger muscle or muscles.

The muscular system is one component of the musculoskeletal system, which includes not only the muscles but also the bones, joints, tendons, and other structures that permit movement.

The three types of muscle (skeletal, cardiac and smooth) have significant differences. However, all three use the movement of actin against myosin to create contraction. In skeletal muscle, contraction is stimulated by electrical impulses transmitted by the nerves, the motoneurons (motor nerves) in particular. Cardiac and smooth muscle contractions are stimulated by internal pacemaker cells which regularly contract, and propagate contractions to other muscle cells they are in contact with. All skeletal muscle and many smooth muscle contractions are facilitated by the neurotransmitter acetylcholine.

The action a muscle generates is determined by the origin and insertion locations. The cross-sectional area of a muscle (rather than volume or length) determines the amount of force it can generate by defining the number of "sarcomeres" which can operate in parallel. Each skeletal muscle contains long units called myofibrils, and each myofibril is a chain of sarcomeres. Since contraction occurs at the same time for all connected sarcomeres in a muscles cell, these chains of sarcomeres shorten together, thus shortening the muscle fiber, resulting in overall length change. [14]The amount of force applied to the external environment is determined by lever mechanics, specifically the ratio of in-lever to out-lever. For example, moving the insertion point of the biceps more distally on the radius (farther from the joint of rotation) would increase the force generated during flexion (and, as a result, the maximum weight lifted in this movement), but decrease the maximum speed of flexion. Moving the insertion point proximally (closer to the joint of rotation) would result in decreased force but increased velocity. This can be most easily seen by comparing the limb of a mole to a horse - in the former, the insertion point is positioned to maximize force (for digging), while in the latter, the insertion point is positioned to maximize speed (for running).

Muscular activity accounts for much of the body's energy consumption. All muscle cells produce adenosine triphosphate (ATP) molecules which are used to power the movement of the myosin heads. Muscles have a short-term store of energy in the form of creatine phosphate which is generated from ATP and can regenerate ATP when needed with creatine kinase. Muscles also keep a storage form of glucose in the form of glycogen. Glycogen can be rapidly converted to glucose when energy is required for sustained, powerful contractions. Within the voluntary skeletal muscles, the glucose molecule can be metabolized anaerobically in a process called glycolysis which produces two ATP and two lactic acid molecules in the process (note that in aerobic conditions, lactate is not formed; instead pyruvate is formed and transmitted through the citric acid cycle). Muscle cells also contain globules of fat, which are used for energy during aerobic exercise. The aerobic energy systems take longer to produce the ATP and reach peak efficiency, and requires many more biochemical steps, but produces significantly more ATP than anaerobic glycolysis. Cardiac muscle on the other hand, can readily consume any of the three macronutrients (protein, glucose and fat) aerobically without a 'warm up' period and always extracts the maximum ATP yield from any molecule involved. The heart, liver and red blood cells will also consume lactic acid produced and excreted by skeletal muscles during exercise.

At rest, skeletal muscle consumes 54.4 kJ/kg(13.0kcal/kg) per day. This is larger than adipose tissue (fat) at 18.8kJ/kg (4.5kcal/kg), and bone at 9.6kJ/kg (2.3kcal/kg).[15]

The efferent leg of the peripheral nervous system is responsible for conveying commands to the muscles and glands, and is ultimately responsible for voluntary movement. Nerves move muscles in response to voluntary and autonomic (involuntary) signals from the brain. Deep muscles, superficial muscles, muscles of the face and internal muscles all correspond with dedicated regions in the primary motor cortex of the brain, directly anterior to the central sulcus that divides the frontal and parietal lobes.

In addition, muscles react to reflexive nerve stimuli that do not always send signals all the way to the brain. In this case, the signal from the afferent fiber does not reach the brain, but produces the reflexive movement by direct connections with the efferent nerves in the spine. However, the majority of muscle activity is volitional, and the result of complex interactions between various areas of the brain.

Nerves that control skeletal muscles in mammals correspond with neuron groups along the primary motor cortex of the brain's cerebral cortex. Commands are routed though the basal ganglia and are modified by input from the cerebellum before being relayed through the pyramidal tract to the spinal cord and from there to the motor end plate at the muscles. Along the way, feedback, such as that of the extrapyramidal system contribute signals to influence muscle tone and response.

Deeper muscles such as those involved in posture often are controlled from nuclei in the brain stem and basal ganglia.

The afferent leg of the peripheral nervous system is responsible for conveying sensory information to the brain, primarily from the sense organs like the skin. In the muscles, the muscle spindles convey information about the degree of muscle length and stretch to the central nervous system to assist in maintaining posture and joint position. The sense of where our bodies are in space is called proprioception, the perception of body awareness. More easily demonstrated than explained, proprioception is the "unconscious" awareness of where the various regions of the body are located at any one time. This can be demonstrated by anyone closing their eyes and waving their hand around. Assuming proper proprioceptive function, at no time will the person lose awareness of where the hand actually is, even though it is not being detected by any of the other senses.

Several areas in the brain coordinate movement and position with the feedback information gained from proprioception. The cerebellum and red nucleus in particular continuously sample position against movement and make minor corrections to assure smooth motion.

The efficiency of human muscle has been measured (in the context of rowing and cycling) at 18% to 26%. The efficiency is defined as the ratio of mechanical work output to the total metabolic cost, as can be calculated from oxygen consumption. This low efficiency is the result of about 40% efficiency of generating ATP from food energy, losses in converting energy from ATP into mechanical work inside the muscle, and mechanical losses inside the body. The latter two losses are dependent on the type of exercise and the type of muscle fibers being used (fast-twitch or slow-twitch). For an overall efficiency of 20 percent, one watt of mechanical power is equivalent to 4.3 kcal per hour. For example, one manufacturer of rowing equipment calibrates its rowing ergometer to count burned calories as equal to four times the actual mechanical work, plus 300 kcal per hour,[16] this amounts to about 20 percent efficiency at 250 watts of mechanical output. The mechanical energy output of a cyclic contraction can depend upon many factors, including activation timing, muscle strain trajectory, and rates of force rise & decay. These can be synthesized experimentally using work loop analysis.

A display of "strength" (e.g. lifting a weight) is a result of three factors that overlap: physiological strength (muscle size, cross sectional area, available crossbridging, responses to training), neurological strength (how strong or weak is the signal that tells the muscle to contract), and mechanical strength (muscle's force angle on the lever, moment arm length, joint capabilities).

Vertebrate muscle typically produces approximately 2533N (5.67.4lbf) of force per square centimeter of muscle cross-sectional area when isometric and at optimal length.[17] Some invertebrate muscles, such as in crab claws, have much longer sarcomeres than vertebrates, resulting in many more sites for actin and myosin to bind and thus much greater force per square centimeter at the cost of much slower speed. The force generated by a contraction can be measured non-invasively using either mechanomyography or phonomyography, be measured in vivo using tendon strain (if a prominent tendon is present), or be measured directly using more invasive methods.

The strength of any given muscle, in terms of force exerted on the skeleton, depends upon length, shortening speed, cross sectional area, pennation, sarcomere length, myosin isoforms, and neural activation of motor units. Significant reductions in muscle strength can indicate underlying pathology, with the chart at right used as a guide.

Since three factors affect muscular strength simultaneously and muscles never work individually, it is misleading to compare strength in individual muscles, and state that one is the "strongest". But below are several muscles whose strength is noteworthy for different reasons.

Humans are genetically predisposed with a larger percentage of one type of muscle group over another. An individual born with a greater percentage of Type I muscle fibers would theoretically be more suited to endurance events, such as triathlons, distance running, and long cycling events, whereas a human born with a greater percentage of Type II muscle fibers would be more likely to excel at sprinting events such as 100 meter dash.[citation needed]

Exercise is often recommended as a means of improving motor skills, fitness, muscle and bone strength, and joint function. Exercise has several effects upon muscles, connective tissue, bone, and the nerves that stimulate the muscles. One such effect is muscle hypertrophy, an increase in size. This is used in bodybuilding.

Various exercises require a predominance of certain muscle fiber utilization over another. Aerobic exercise involves long, low levels of exertion in which the muscles are used at well below their maximal contraction strength for long periods of time (the most classic example being the marathon). Aerobic events, which rely primarily on the aerobic (with oxygen) system, use a higher percentage of Type I (or slow-twitch) muscle fibers, consume a mixture of fat, protein and carbohydrates for energy, consume large amounts of oxygen and produce little lactic acid. Anaerobic exercise involves short bursts of higher intensity contractions at a much greater percentage of their maximum contraction strength. Examples of anaerobic exercise include sprinting and weight lifting. The anaerobic energy delivery system uses predominantly Type II or fast-twitch muscle fibers, relies mainly on ATP or glucose for fuel, consumes relatively little oxygen, protein and fat, produces large amounts of lactic acid and can not be sustained for as long a period as aerobic exercise. Many exercises are partially aerobic and partially anaerobic; for example, soccer and rock climbing involve a combination of both.

The presence of lactic acid has an inhibitory effect on ATP generation within the muscle; though not producing fatigue, it can inhibit or even stop performance if the intracellular concentration becomes too high. However, long-term training causes neovascularization within the muscle, increasing the ability to move waste products out of the muscles and maintain contraction. Once moved out of muscles with high concentrations within the sarcomere, lactic acid can be used by other muscles or body tissues as a source of energy, or transported to the liver where it is converted back to pyruvate. In addition to increasing the level of lactic acid, strenuous exercise causes the loss of potassium ions in muscle and causing an increase in potassium ion concentrations close to the muscle fibres, in the interstitium. Acidification by lactic acid may allow recovery of force so that acidosis may protect against fatigue rather than being a cause of fatigue.[19]

Delayed onset muscle soreness is pain or discomfort that may be felt one to three days after exercising and generally subsides two to three days later. Once thought to be caused by lactic acid build-up, a more recent theory is that it is caused by tiny tears in the muscle fibers caused by eccentric contraction, or unaccustomed training levels. Since lactic acid disperses fairly rapidly, it could not explain pain experienced days after exercise.[20]

Independent of strength and performance measures, muscles can be induced to grow larger by a number of factors, including hormone signaling, developmental factors, strength training, and disease. Contrary to popular belief, the number of muscle fibres cannot be increased through exercise. Instead, muscles grow larger through a combination of muscle cell growth as new protein filaments are added along with additional mass provided by undifferentiated satellite cells alongside the existing muscle cells.[13]

Biological factors such as age and hormone levels can affect muscle hypertrophy. During puberty in males, hypertrophy occurs at an accelerated rate as the levels of growth-stimulating hormones produced by the body increase. Natural hypertrophy normally stops at full growth in the late teens. As testosterone is one of the body's major growth hormones, on average, men find hypertrophy much easier to achieve than women. Taking additional testosterone or other anabolic steroids will increase muscular hypertrophy.

Muscular, spinal and neural factors all affect muscle building. Sometimes a person may notice an increase in strength in a given muscle even though only its opposite has been subject to exercise, such as when a bodybuilder finds her left biceps stronger after completing a regimen focusing only on the right biceps. This phenomenon is called cross education.[citation needed]

Inactivity and starvation in mammals lead to atrophy of skeletal muscle, a decrease in muscle mass that may be accompanied by a smaller number and size of the muscle cells as well as lower protein content.[21] Muscle atrophy may also result from the natural aging process or from disease.

In humans, prolonged periods of immobilization, as in the cases of bed rest or astronauts flying in space, are known to result in muscle weakening and atrophy. Atrophy is of particular interest to the manned spaceflight community, because the weightlessness experienced in spaceflight results is a loss of as much as 30% of mass in some muscles.[22][23] Such consequences are also noted in small hibernating mammals like the golden-mantled ground squirrels and brown bats.[24]

During aging, there is a gradual decrease in the ability to maintain skeletal muscle function and mass, known as sarcopenia. The exact cause of sarcopenia is unknown, but it may be due to a combination of the gradual failure in the "satellite cells" that help to regenerate skeletal muscle fibers, and a decrease in sensitivity to or the availability of critical secreted growth factors that are necessary to maintain muscle mass and satellite cell survival. Sarcopenia is a normal aspect of aging, and is not actually a disease state yet can be linked to many injuries in the elderly population as well as decreasing quality of life.[25]

There are also many diseases and conditions that cause muscle atrophy. Examples include cancer and AIDS, which induce a body wasting syndrome called cachexia. Other syndromes or conditions that can induce skeletal muscle atrophy are congestive heart disease and some diseases of the liver.

Neuromuscular diseases are those that affect the muscles and/or their nervous control. In general, problems with nervous control can cause spasticity or paralysis, depending on the location and nature of the problem. A large proportion of neurological disorders, ranging from cerebrovascular accident (stroke) and Parkinson's disease to CreutzfeldtJakob disease, can lead to problems with movement or motor coordination.

Symptoms of muscle diseases may include weakness, spasticity, myoclonus and myalgia. Diagnostic procedures that may reveal muscular disorders include testing creatine kinase levels in the blood and electromyography (measuring electrical activity in muscles). In some cases, muscle biopsy may be done to identify a myopathy, as well as genetic testing to identify DNA abnormalities associated with specific myopathies and dystrophies.

A non-invasive elastography technique that measures muscle noise is undergoing experimentation to provide a way of monitoring neuromuscular disease. The sound produced by a muscle comes from the shortening of actomyosin filaments along the axis of the muscle. During contraction, the muscle shortens along its longitudinal axis and expands across the transverse axis, producing vibrations at the surface.[26]

The evolutionary origin of muscle cells in metazoans is a highly debated topic. In one line of thought scientists have believed that muscle cells evolved once and thus all animals with muscles cells have a single common ancestor. In the other line of thought, scientists believe muscles cells evolved more than once and any morphological or structural similarities are due to convergent evolution and genes that predate the evolution of muscle and even the mesoderm - the germ layer from which many scientists believe true muscle cells derive.

Schmid and Seipel argue that the origin of muscle cells is a monophyletic trait that occurred concurrently with the development of the digestive and nervous systems of all animals and that this origin can be traced to a single metazoan ancestor in which muscle cells are present. They argue that molecular and morphological similarities between the muscles cells in cnidaria and ctenophora are similar enough to those of bilaterians that there would be one ancestor in metazoans from which muscle cells derive. In this case, Schmid and Seipel argue that the last common ancestor of bilateria, ctenophora, and cnidaria was a triploblast or an organism with three germ layers and that diploblasty, meaning an organism with two germ layers, evolved secondarily due to their observation of the lack of mesoderm or muscle found in most cnidarians and ctenophores. By comparing the morphology of cnidarians and ctenophores to bilaterians, Schmid and Seipel were able to conclude that there were myoblast-like structures in the tentacles and gut of some species of cnidarians and in the tentacles of ctenophores. Since this is a structure unique to muscle cells, these scientists determined based on the data collected by their peers that this is a marker for striated muscles similar to that observed in bilaterians. The authors also remark that the muscle cells found in cnidarians and ctenophores are often contests due to the origin of these muscle cells being the ectoderm rather than the mesoderm or mesendoderm. The origin of true muscles cells is argued by others to be the endoderm portion of the mesoderm and the endoderm. However, Schmid and Seipel counter this skepticism about whether or not the muscle cells found in ctenophores and cnidarians are true muscle cells by considering that cnidarians develop through a medusa stage and polyp stage. They observe that in the hydrozoan medusa stage there is a layer of cells that separate from the distal side of the ectoderm to form the striated muscle cells in a way that seems similar to that of the mesoderm and call this third separated layer of cells the ectocodon. They also argue that not all muscle cells are derived from the mesendoderm in bilaterians with key examples being that in both the eye muscles of vertebrates and the muscles of spiralians these cells derive from the ectodermal mesoderm rather than the endodermal mesoderm. Furthermore, Schmid and Seipel argue that since myogenesis does occur in cnidarians with the help of molecular regulatory elements found in the specification of muscles cells in bilaterians that there is evidence for a single origin for striated muscle.[27]

In contrast to this argument for a single origin of muscle cells, Steinmetz et al. argue that molecular markers such as the myosin II protein used to determine this single origin of striated muscle actually predate the formation of muscle cells. This author uses an example of the contractile elements present in the porifera or sponges that do truly lack this striated muscle containing this protein. Furthermore, Steinmetz et al. present evidence for a polyphyletic origin of striated muscle cell development through their analysis of morphological and molecular markers that are present in bilaterians and absent in cnidarians, ctenophores, and bilaterians. Steimetz et al. showed that the traditional morphological and regulatory markers such as actin, the ability to couple myosin side chains phosphorylation to higher concentrations of the positive concentrations of calcium, and other MyHC elements are present in all metazoans not just the organisms that have been shown to have muscle cells. Thus, the usage of any of these structural or regulatory elements in determining whether or not the muscle cells of the cnidarians and ctenophores are similar enough to the muscle cells of the bilaterians to confirm a single lineage is questionable according to Steinmetz et al. Furthermore, Steinmetz et al. explain that the orthologues of the MyHc genes that have been used to hypothesize the origin of striated muscle occurred through a gene duplication event that predates the first true muscle cells (meaning striated muscle), and they show that the MyHc genes are present in the sponges that have contractile elements but no true muscle cells. Furthermore, Steinmetz et all showed that the localization of this duplicated set of genes that serve both the function of facilitating the formation of striated muscle genes and cell regulation and movement genes were already separated into striated myhc and non-muscle myhc. This separation of the duplicated set of genes is shown through the localization of the striated myhc to the contractile vacuole in sponges while the non-muscle myhc was more diffusely expressed during developmental cell shape and change. Steinmetz et al. found a similar pattern of localization in cnidarians with except with the cnidarian N. vectensis having this striated muscle marker present in the smooth muscle of the digestive track. Thus, Steinmetz et al. argue that the pleisiomorphic trait of the separated orthologues of myhc cannot be used to determine the monophylogeny of muscle, and additionally argue that the presence of a striated muscle marker in the smooth muscle of this cnidarian shows a fundamentally different mechanism of muscle cell development and structure in cnidarians.[28]

Steinmetz et al. continue to argue for multiple origins of striated muscle in the metazoans by explaining that a key set of genes used to form the troponin complex for muscle regulation and formation in bilaterians is missing from the cnidarians and ctenophores, and of 47 structural and regulatory proteins observed, Steinmetz et al. were not able to find even on unique striated muscle cell protein that was expressed in both cnidarians and bilaterians. Furthermore, the Z-disc seemed to have evolved differently even within bilaterians and there is a great deal diversity of proteins developed even between this clade, showing a large degree of radiation for muscle cells. Through this divergence of the Z-disc, Steimetz et al. argue that there are only four common protein components that were present in all bilaterians muscle ancestors and that of these for necessary Z-disc components only an actin protein that they have already argued is an uninformative marker through its pleisiomorphic state is present in cnidarians. Through further molecular marker testing, Steinmetz et al. observe that non-bilaterians lack many regulatory and structural components necessary for bilaterians muscle formation and do not find any unique set of proteins to both bilaterians and cnidarians and ctenophores that are not present in earlier, more primitive animals such as the sponges and amoebozoans. Through this analysis the authors conclude that due to the lack of elements that bilaterians muscles are dependent on for structure and usage, nonbilaterian muscles must be of a different origin with a different set regulatory and structural proteins.[28]

In another take on the argument, Andrikou and Arnone use the newly available data on gene regulatory networks to look at how the hierarchy of genes and morphogens and other mechanism of tissue specification diverge and are similar among early deuterostomes and protostomes. By understanding not only what genes are present in all bilaterians but also the time and place of deployment of these genes, Andrikou and Arnone discuss a deeper understanding of the evolution of myogenesis.[29]

In their paper Andrikou and Arnone argue that to truly understand the evolution of muscle cells the function of transcriptional regulators must be understood in the context of other external and internal interactions. Through their analysis, Andrikou and Arnone found that there were conserved orthologues of the gene regulatory network in both invertebrate bilaterians and in cnidarians. They argue that having this common, general regulatory circuit allowed for a high degree of divergence from a single well functioning network. Andrikou and Arnone found that the orthologues of genes found in vertebrates had been changed through different types of structural mutations in the invertebrate deuterostomes and protostomes, and they argue that these structural changes in the genes allowed for a large divergence of muscle function and muscle formation in these species. Andrikou and Arnone were able to recognize not only any difference due to mutation in the genes found in vertebrates and invertebrates but also the integration of species specific genes that could also cause divergence from the original gene regulatory network function. Thus, although a common muscle patterning system has been determined, they argue that this could be due to a more ancestral gene regulatory network being coopted several times across lineages with additional genes and mutations causing very divergent development of muscles. Thus it seems that myogenic patterning framework may be an ancestral trait. However, Andrikou and Arnone explain that the basic muscle patterning structure must also be considered in combination with the cis regulatory elements present at different times during development. In contrast with the high level of gene family apparatuses structure, Andrikou and Arnone found that the cis regulatory elements were not well conserved both in time and place in the network which could show a large degree of divergence in the formation of muscle cells. Through this analysis, it seems that the myogenic GRN is an ancestral GRN with actual changes in myogenic function and structure possibly being linked to later coopts of genes at different times and places.[29]

Evolutionarily, specialized forms of skeletal and cardiac muscles predated the divergence of the vertebrate/arthropod evolutionary line.[30][dead link] This indicates that these types of muscle developed in a common ancestor sometime before 700 million years ago (mya). Vertebrate smooth muscle was found to have evolved independently from the skeletal and cardiac muscle types.

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Insulin resistance reversed by removal of Gal3 protein By removing the protein galectin-3 (Gal3), a team of investigators were able to reverse diabetic insulin resistance and glucose intolerance in mice used as models of obesity and diabetes.

Nov 16, 2016-----News ArchiveLatest research covered daily, archived weekly

B12 deficiency can increase risk for type 2 diabetes B12 deficiency during pregnancy may predispose baby into adulthood for metabolic problems such as type-2 diabetes.

Nov 15, 2016-----News ArchiveLatest research covered daily, archived weekly

Non-invasive prenatal test at five weeks of pregnancy? The latest developments in prenatal technology may make it possible to test for genetic disorders one month into pregnancy.

Nov 14, 2016-----News ArchiveLatest research covered daily, archived weekly

Heart disease, leukemia links to dysfunctional nucleus In cells, the nucleus keeps DNA protected and intact within an enveloping membrane. But a new study reveals that this containment influences how genes are expressed.

Nov 11, 2016-----News ArchiveLatest research covered daily, archived weekly

Blood vessels control brain growth Blood vessels play a vital role in stem cell reproduction, enabling the brain to grow and develop in the womb, reveals new research in mice.

Nov 10, 2016-----News ArchiveLatest research covered daily, archived weekly

Antibody protects developing fetus from Zika virusThe most devastating consequence of Zika virus is the development of microcephaly, an abnormally small head, in babies infected in utero. Now, research has identified a human antibody preventing pregnant mice, from infecting the fetus with Zika and damaging the placenta. It also protects adult mice from the Zika disease.

Nov 9, 2016-----News ArchiveLatest research covered daily, archived weekly

Better treatments possible for child brain cancer More than 4,000 children and teens are diagnosed with brain cancer yearly, killing more children than any other cancer. Researchers targeted an aggressive pediatric brain tumor CNS-PNET using a zebrafish model. And, in about 80% of cases, eliminated the tumor using existing drugs.

Nov 8, 2016-----News ArchiveLatest research covered daily, archived weekly

Autism linked to mutations in mitochondrial DNA Study of 903 affected children shows inherited, spontaneous mutations increase the risk of autism spectrum disorder (ASD). The children diagnosed with autism had greater numbers of harmful mutations in their mitochondrial DNA than other family members.

Nov 7, 2016-----News ArchiveLatest research covered daily, archived weekly

Mother's blood test may predict birth complications DLK1 protein found in the blood of pregnant women could be developed to test the health of babies and aid in decisions on early elective deliveries, according to a study led by Queen Mary University of London.

Nov 4, 2016-----News ArchiveLatest research covered daily, archived weekly

Essential mouse genes give insight into human disease About a third of all genes in mammals are essential to life. Now an international, multi-institutional team, describes their discovery of which genes they are and what impact they make on human development and disease.

Nov 3, 2016-----News ArchiveLatest research covered daily, archived weekly

Newborns given dextrose gel avoid hypoglycaemia A single dose of dextrose gel, rubbed inside a newborn baby's mouth an hour after birth, can lower the risk for developing neonatal hypoglycaemia, according to a randomized study.

Nov 2, 2016-----News ArchiveLatest research covered daily, archived weekly

Mitochondria divide differently than once thought For the first time a study reveals how mitochondria, the power generators found in nearly all living cells, regularly divide and multiply.

Nov 1, 2016-----News ArchiveLatest research covered daily, archived weekly

Customizing vitamin D may benefit pregnant women Individualized vitamin D supplements help protect pregnant women from its deficiency. Tailored doses may compensate for individual risk factors and even protect bones.

Oct 31, 2016-----News ArchiveLatest research covered daily, archived weekly

Antibody breaks leukemia's hold In mouse models and patient cells, anti-CD98 antibody disrupts interactions between leukemia cells and surrounding blood vessels, inhibiting cancer's spread.

Oct 28, 2016-----News ArchiveLatest research covered daily, archived weekly

Strong, steady forces needed for cell divisionBiologists studying cell division have long disagreed about how much force is needed to pull chromosomes apart in order to form two new cells. A question fundamental to how cells divide.

Oct 27, 2016-----News ArchiveLatest research covered daily, archived weekly

"Fixing" energy signals to treat mitochondrial disease Restoring cellular energy signals may offset mitochondrial diseases in humans. Using existing drugs to treat lab animals, researchers have set the stage for clinical trials.

Oct 26, 2016-----News ArchiveLatest research covered daily, archived weekly

How eggs get the wrong number of chromosomes Twentyfour hours before ovulation, human oocytes start to divide into what will become mature eggs. Ideally, eggs include a complete set of 23 chromosomes, but the process is prone to error especially as women age.

Oct 25, 2016-----News ArchiveLatest research covered daily, archived weekly

Fatal preemie disease due to mitochondrial failure A life-threatening condition preventing gut development in premature infants may be triggered by a disruption in the way the body metabolizes energy from Mitochondria.

Oct 24, 2016-----News ArchiveLatest research covered daily, archived weekly

Zika virus spread timed to brain growth spurts Scientists from the Florida campus of The Scripps Research Institute (TSRI) are able to pinpoint timing of the most aggressive ZIKA attacks on newborn mouse brains information that could help treatments.

Oct 21, 2016-----News ArchiveLatest research covered daily, archived weekly

Short jump from single-cell to multi-cell animals Our single-celled ancestors lived about 800 million years ago. Now, new evidence suggests their leap to multi-celled organisms was not quite as mysterious as once believed.

Oct 20, 2016-----News ArchiveLatest research covered daily, archived weekly

Brainstem and visual cortex control our eyes A mouse study is illuminating how our brain quickly adapts and functions. Tracking mouse eye movements, researchers make an unexpected discovery the part of the brain known to process sensory information, our visual cortex, is also key to spontaneous eye movements.

Oct 19, 2016-----News ArchiveLatest research covered daily, archived weekly

Embryos make sex cells in their first two weeks Producing the next generation of life is already occuring in an embryo in its own first weeks. Human primordial germ cells which give rise to sperm or egg cells are present in embryos by their second week of development.

Oct 18, 2016-----News ArchiveLatest research covered daily, archived weekly

Mom's BMI may affect biological age of her baby Higher Body Mass Index (BMI) in a mother before pregnancy is associated with shorter telomere length a biomarker for biological age in her newborn. Her baby's short telomere length means the baby's cells have shorter lifespans.

Oct 17, 2016-----News ArchiveLatest research covered daily, archived weekly

Two distinct cell types can initiate Crohn's disease A new discovery could lead to personalized treatment for the debilitating gastrointestinal disorder called Crohn's. There appear to be two distinct disease types. One expressed in normal colon tissue, the other in the small intestine. Detecting which type a patient has will assist her in her treatment and desire to get pregnant or carry a pregnancy.

Oct 14, 2016-----News ArchiveLatest research covered daily, archived weekly

Potential treatment of newborns via amniotic fluid? A breakthrough study offers promise for therapeutic management of congenital diseases in utero using designer gene sequences.

Oct 13, 2016-----News ArchiveLatest research covered daily, archived weekly

Infants use their prefrontal cortex to learn Researchers have always thought the prefrontal cortex (PFC) the brain region involved in some of the highest forms of cognition and reasoning was too underdeveloped in young children, especially infants, to participate in complex cognitive tasks. A new study suggests otherwise.

Oct 12, 2016-----News ArchiveLatest research covered daily, archived weekly

'Amplifier' helps make connections in the fetal brain A special amplifier makes neural signals stronger in babies then stops once neural connections are fully strengthened. Oct 11, 2016-----News ArchiveLatest research covered daily, archived weekly

Neurons migrate throughout infancy A previously unrecognized stage of brain development has just been recognized to continue long after birth. Neurons in the cerebral cortex, the outer layer of the brain, migrate into the cortex continuing growth throughout infancy.

Oct 10, 2016-----News ArchiveLatest research covered daily, archived weekly

Calcium triggers stem cells to generate bone Calcium is the main constituent of bone, and now is found to play a major role in regulating its growth. This new finding may affect treatment of conditions caused by too much collagen, such as fibrosis which thickens and scars connective tissue, as well in diseases of too little bone growth, such as Treacher Collins Syndrome (TCS).

Oct 7, 2016-----News ArchiveLatest research covered daily, archived weekly

How evolution has given us 5 fingers Have you ever wondered why our hands have exactly five fingers? Dr. Marie Kmita's team has. The researchers at the Institut de recherches cliniques de Montral and Universit de Montral have uncovered a part of this mystery.

Oct 6, 2016-----News ArchiveLatest research covered daily, archived weekly New links between genes and bigger brains A number of new links between genes and brain size have been identified by United Kingdom scientists, hopefully opening up whole new avenues of understanding brain development including diseases like dementia.

Oct 5, 2016-----News ArchiveLatest research covered daily, archived weekly Progesterone in contraceptives promotes flu healing Over 100 million women are on hormonal contraceptives. All contain some form of progesterone, either alone or in combination with estrogen. Researchers found treatment with progesterone protects female mice against influenza by reducing inflammation and improving pulmonary function.

Oct 4, 2016-----News ArchiveLatest research covered daily, archived weekly

ZIKA in Men? "No procreation for 6 months" The Zika virus has largely spread via mosquitoes, but it can also be spread by sexual intercourse. Men who may have been exposed should wait at least six months before trying to conceive a child with a partner. Regardless whether they ever had any symptoms, say US federal health officials.

Oct 3, 2016-----News ArchiveLatest research covered daily, archived weekly Genetically modified baby boy - with 3 parents New, cheap and accurate DNA-editing techniques called CRISPR-Cas9 and SNT, or single nucleic targeting, are allowing for gene modification in humans. It is not science fiction anymore. In a first, a baby boy with modified DNA has been born in Mexico to overcome a mitochondrial disease that claimed the life of his two earlier sibblings

Sep 30, 2016-----News ArchiveLatest research covered daily, archived weekly Meet the world's largest bony fish For the first time, the genome of the ocean sunfish (Mola mola), the world's largest bony fish, has been sequenced. Researchers involved in the Genome 10K (G10K) project want to collect 10,000 nonmammalian vertebrate genomes for comparative analyses. The ocean sunfish genome has now revealed several altered genes that may explain its' fast growth, large size and unusual shape.

Sep 29, 2016-----News ArchiveLatest research covered daily, archived weekly

Genetic variations that cause skull-fusion disorders During the first year of life, the human brain doubles in size, continuing to grow through adolescence. But sometimes, the loosely connected plates of a baby's skull fuse too early, a disorder known as craniosynostosis. It can also produce facial and skull deformities, potentially damaging a young brain.

Sep 28, 2016-----News ArchiveLatest research covered daily, archived weekly

Heart defect genes both inside and outside the heart Congenital heart defects (CHDs) are a leading cause of birth defect-related deaths. How genetic alterations cause such defects is complicated by the fact that CHD's many critical genes are unknown. Those that are known often contribute only small increases in CHD risk.

Sep 27, 2016-----News ArchiveLatest research covered daily, archived weekly Cesarean baby 15% more likely to become obese Cesarean born babies are 15% more likely to become obese as children than individuals born by vaginal birth and 64% more likely to be obese than their siblings born by vaginal birth. The increased risk may persist through adulthood. All of this data is according to a large study from Harvard T.H. Chan School of Public Health.

Sep 26, 2016-----News ArchiveLatest research covered daily, archived weekly

Male primes female for reproduction - but at a cost Research has discovered that male worms, through an invisible chemical "essence," prime female worms for reproduction but with the unfortunate side effect of also hastening her aging. The results might lead to human therapies to delay puberty or prolong fertility.

Sep 23, 2016-----News ArchiveLatest research covered daily, archived weekly Why Tardigrades Are So Indestructible Tardigrades, or water bears, are microscopic animals capable of withstanding some of the most severe environmental conditions even being "dead" for 30 years, and then restored to life! Research from Japan has now created the most accurate picture yet of the tardigrade genome and why it matters to humans.

Sep 22, 2016-----News ArchiveLatest research covered daily, archived weekly Mouse bone marrow cells reduce miscarriage? Progenitor cells are like stem cells, but differentiated by a first step into one specific cell type. Research now finds the progenitor cells in bone marrow which replace worn out cells may help placental blood vessel growth and reduce abnormal placental development such as in pre-eclampsia.

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Welcome to The Visible Embryo

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Adipose tissue – Wikipedia

Friday, December 2nd, 2016

In biology, adipose tissue i, body fat, or simply fat is a loose connective tissue composed mostly of adipocytes.[1] In addition to adipocytes, adipose tissue contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular endothelial cells and a variety of immune cells such as adipose tissue macrophages. Adipose tissue is derived from preadipocytes. Its main role is to store energy in the form of lipids, although it also cushions and insulates the body. Far from being hormonally inert, adipose tissue has, in recent years, been recognized as a major endocrine organ,[2] as it produces hormones such as leptin, estrogen, resistin, and the cytokine TNF. The two types of adipose tissue are white adipose tissue (WAT), which stores energy, and brown adipose tissue (BAT), which generates body heat. The formation of adipose tissue appears to be controlled in part by the adipose gene. Adipose tissue more specifically brown adipose tissue was first identified by the Swiss naturalist Conrad Gessner in 1551.[3]

In humans, adipose tissue is located beneath the skin (subcutaneous fat), around internal organs (visceral fat), in bone marrow (yellow bone marrow), intermuscular (Muscular system) and in the breast tissue. Adipose tissue is found in specific locations, which are referred to as adipose depots. Apart from adipocytes, which comprise the highest percentage of cells within adipose tissue, other cell types are present, collectively termed stromal vascular fraction (SVF) of cells. SVF includes preadipocytes, fibroblasts, adipose tissue macrophages, and endothelial cells. Adipose tissue contains many small blood vessels. In the integumentary system, which includes the skin, it accumulates in the deepest level, the subcutaneous layer, providing insulation from heat and cold. Around organs, it provides protective padding. However, its main function is to be a reserve of lipids, which can be burned to meet the energy needs of the body and to protect it from excess glucose by storing triglycerides produced by the liver from sugars, although some evidence suggests that most lipid synthesis from carbohydrates occurs in the adipose tissue itself.[4] Adipose depots in different parts of the body have different biochemical profiles. Under normal conditions, it provides feedback for hunger and diet to the brain.

Mice have eight major adipose depots, four of which are within the abdominal cavity.[1] The paired gonadal depots are attached to the uterus and ovaries in females and the epididymis and testes in males; the paired retroperitoneal depots are found along the dorsal wall of the abdomen, surrounding the kidney, and, when massive, extend into the pelvis. The mesenteric depot forms a glue-like web that supports the intestines and the omental depot (which originates near the stomach and spleen) and- when massive- extends into the ventral abdomen. Both the mesenteric and omental depots incorporate much lymphoid tissue as lymph nodes and milky spots, respectively. The two superficial depots are the paired inguinal depots, which are found anterior to the upper segment of the hind limbs (underneath the skin) and the subscapular depots, paired medial mixtures of brown adipose tissue adjacent to regions of white adipose tissue, which are found under the skin between the dorsal crests of the scapulae. The layer of brown adipose tissue in this depot is often covered by a "frosting" of white adipose tissue; sometimes these two types of fat (brown and white) are hard to distinguish. The inguinal depots enclose the inguinal group of lymph nodes. Minor depots include the pericardial, which surrounds the heart, and the paired popliteal depots, between the major muscles behind the knees, each containing one large lymph node.[5] Of all the depots in the mouse, the gonadal depots are the largest and the most easily dissected,[6] comprising about 30% of dissectible fat.[7]

In an obese person, excess adipose tissue hanging downward from the abdomen is referred to as a panniculus (or pannus). A panniculus complicates surgery of the morbidly obese individual. It may remain as a literal "apron of skin" if a severely obese person quickly loses large amounts of fat (a common result of gastric bypass surgery). This condition cannot be effectively corrected through diet and exercise alone, as the panniculus consists of adipocytes and other supporting cell types shrunken to their minimum volume and diameter.[citation needed] Reconstructive surgery is one method of treatment.

Visceral fat or abdominal fat[8] (also known as organ fat or intra-abdominal fat) is located inside the abdominal cavity, packed between the organs (stomach, liver, intestines, kidneys, etc.). Visceral fat is different from subcutaneous fat underneath the skin, and intramuscular fat interspersed in skeletal muscles. Fat in the lower body, as in thighs and buttocks, is subcutaneous and is not consistently spaced tissue, whereas fat in the abdomen is mostly visceral and semi-fluid.[9] Visceral fat is composed of several adipose depots, including mesenteric, epididymal white adipose tissue (EWAT), and perirenal depots. Visceral fat is often expressed in terms of its area in cm2 (VFA, visceral fat area).[10]

An excess of visceral fat is known as central obesity, or "belly fat", in which the abdomen protrudes excessively and new developments such as the Body Volume Index (BVI) are specifically designed to measure abdominal volume and abdominal fat. Excess visceral fat is also linked to type 2 diabetes,[11]insulin resistance,[12]inflammatory diseases,[13] and other obesity-related diseases.[14] Likewise, the accumulation of neck fat (or cervical adipose tissue) has been shown to be associated with mortality.[15]

Men are more likely to have fat stored in the abdomen due to sex hormone differences. Female sex hormone causes fat to be stored in the buttocks, thighs, and hips in women.[16][17] When women reach menopause and the estrogen produced by the ovaries declines, fat migrates from the buttocks, hips and thighs to the waist;[18] later fat is stored in the abdomen.[19]

High-intensity exercise is one way to effectively reduce total abdominal fat.[20][21] One study suggests at least 10 MET-hours per week of aerobic exercise is required for visceral fat reduction.[22]

Epicardial adipose tissue (EAT) is a particular form of visceral fat deposited around the heart and found to be a metabolically active organ that generates various bioactive molecules, which might significantly affect cardiac function.[23] Marked component differences have been observed in comparing EAT with subcutaneous fat, suggesting a depot specific impact of stored fatty acids on adipocyte function and metabolism.[24]

Most of the remaining nonvisceral fat is found just below the skin in a region called the hypodermis.[25] This subcutaneous fat is not related to many of the classic obesity-related pathologies, such as heart disease, cancer, and stroke, and some evidence even suggests it might be protective.[26] The typically female (or gynecoid) pattern of body fat distribution around the hips, thighs, and buttocks is subcutaneous fat, and therefore poses less of a health risk compared to visceral fat.[27]

Like all other fat organs, subcutaneous fat is an active part of the endocrine system, secreting the hormones leptin and resistin.[25]

The relationship between the subcutaneous adipose layer and total body fat in a person is often modelled by using regression equations. The most popular of these equations was formed by Durnin and Wormersley, who rigorously tested many types of skinfold, and, as a result, created two formulae to calculate the body density of both men and women. These equations present an inverse correlation between skinfolds and body densityas the sum of skinfolds increases, the body density decreases.[28]

Factors such as sex, age, population size or other variables may make the equations invalid and unusable, and, as of 2012[update], Durnin and Wormersley's equations remain only estimates of a person's true level of fatness. New formulae are still being created.[28]

Ectopic fat is the storage of triglycerides in tissues other than adipose tissue, that are supposed to contain only small amounts of fat, such as the liver, skeletal muscle, heart, and pancreas.[1] This can interfere with cellular functions and hence organ function and is associated with insulin resistance in type-2 diabetes.[29] It is stored in relatively high amounts around the organs of the abdominal cavity, but is not to be confused as visceral fat.

The specific cause for the accumulation of ectopic fat is unknown. The cause is likely a combination of genetic, environmental, and behavioral factors that are involved in excess energy intake and decreased physical activity. Substantial weight loss can reduce ectopic fat stores in all organs and this is associated with an improvement of the function of that organ.[29]

Free fatty acids are liberated from lipoproteins by lipoprotein lipase (LPL) and enter the adipocyte, where they are reassembled into triglycerides by esterifying it onto glycerol. Human fat tissue contains about 87% lipids[citation needed].

There is a constant flux of FFA (Free Fatty Acids) entering and leaving adipose tissue. The net direction of this flux is controlled by insulin and leptinif insulin is elevated, then there is a net inward flux of FFA, and only when insulin is low can FFA leave adipose tissue. Insulin secretion is stimulated by high blood sugar, which results from consuming carbohydrates.

In humans, lipolysis (hydrolysis of triglycerides into free fatty acids) is controlled through the balanced control of lipolytic B-adrenergic receptors and a2A-adrenergic receptor-mediated antilipolysis.

Fat cells have an important physiological role in maintaining triglyceride and free fatty acid levels, as well as determining insulin resistance. Abdominal fat has a different metabolic profilebeing more prone to induce insulin resistance. This explains to a large degree why central obesity is a marker of impaired glucose tolerance and is an independent risk factor for cardiovascular disease (even in the absence of diabetes mellitus and hypertension).[30] Studies of female monkeys at Wake Forest University (2009) discovered that individuals suffering from higher stress have higher levels of visceral fat in their bodies. This suggests a possible cause-and-effect link between the two, wherein stress promotes the accumulation of visceral fat, which in turn causes hormonal and metabolic changes that contribute to heart disease and other health problems.[31]

Recent advances in biotechnology have allowed for the harvesting of adult stem cells from adipose tissue, allowing stimulation of tissue regrowth using a patient's own cells. In addition, adipose-derived stem cells from both human and animals reportedly can be efficiently reprogrammed into induced pluripotent stem cells without the need for feeder cells.[32] The use of a patient's own cells reduces the chance of tissue rejection and avoids ethical issues associated with the use of human embryonic stem cells.[33] A growing body of evidence also suggests that different fat depots (i.e. abdominal, omental, pericardial) yield adipose-derived stem cells with different characteristics.[33][34] These depot-dependent features include proliferation rate, immunophenotype, differentiation potential, gene expression, as well as sensitivity to hypoxic culture conditions.[35]

Adipose tissue is the greatest peripheral source of aromatase in both males and females,[citation needed] contributing to the production of estradiol.

Adipose derived hormones include:

Adipose tissues also secrete a type of cytokines (cell-to-cell signalling proteins) called adipokines (adipocytokines), which play a role in obesity-associated complications. Perivascular adipose tissue releases adipokines such as adiponectin that affect the contractile function of the vessels that they surround.[1][36]

Brown fat or brown adipose tissue is a specialized form of adipose tissue in humans and other mammals.[37] It is located mainly around the neck and large blood vessels of the thorax. This specialized tissue can generate heat by "uncoupling" the respiratory chain of oxidative phosphorylation within mitochondria. The process of uncoupling means that when protons transit down the electrochemical gradient across the inner mitochondrial membrane, the energy from this process is released as heat rather than being used to generate ATP. This thermogenic process may be vital in neonates exposed to cold, which then require this thermogenesis to keep warm, as they are unable to shiver, or take other actions to keep themselves warm.[38]

Attempts to simulate this process pharmacologically have so far been unsuccessful. Techniques to manipulate the differentiation of "brown fat" could become a mechanism for weight loss therapy in the future, encouraging the growth of tissue with this specialized metabolism without inducing it in other organs.

Until recently, brown adipose tissue was thought to be primarily limited to infants in humans, but new evidence has now overturned that belief. Metabolically active tissue with temperature responses similar to brown adipose was first reported in the neck and trunk of some human adults in 2007,[39] and the presence of brown adipose in human adults was later verified histologically in the same anatomical regions.[40][41][42]

Browning of WAT, also referred to as beiging, occurs when adipocytes within WAT depots develop features of BAT. Beige adipocytes take on a multilocular appearance (containing several lipid droplets) and increase expression of uncoupling protein 1 (UCP1).[43] In doing so, these normally energy-storing adipocytes become energy-releasing adipocytes.

UCP1 is a protein predominantly found in BAT.[44] It acts to dissipate the proton gradient generated by oxidative phosphorylation, leading to the production of heat. Release of catecholamines from sympathetic nerves results in UCP1 activation and usually occurs after extended periods of cold exposure or in response to overfeeding.[45] UCP1 activity is stimulated by long chain fatty acids that are produced subsequent to -adrenergic receptor activation.[46] UCP1 is proposed to function as a fatty acid proton symporter, although the exact mechanism has yet to be elucidated.[47] In contrast, UCP1 is inhibited by ATP, ADP, and GTP.[48]

The calorie-burning capacity of brown and beige fat has been extensively studied as research efforts focus on therapies targeted to treat obesity and diabetes. The drug 2,4-dinitrophenol, which also acts as a chemical uncoupler similarly to UCP1, was used for weight loss in the 1930s. However, it was quickly discontinued when excessive dosing led to adverse side effects including hyperthermia and death.[43] 3 agonists, like CL316,243, have also been developed and tested in humans. However, the use of such drugs has proven largely unsuccessful due to several challenges, including varying species receptor specificity and poor oral bioavailability.[49]

Cold is a primary regulator of BAT processes and induces WAT browning. Browning in response to chronic cold exposure has been well documented and is a reversible process. A study in mice demonstrated that cold-induced browning can be completely reversed in 21 days, with measurable decreases in UCP1 seen within a 24 hour period.[50] A study by Rosenwald et al. revealed that when the animals are re-exposed to a cold environment, the same adipocytes will adopt a beige phenotype, suggesting that beige adipocytes are retained.[51]

Transcriptional regulators, as well as a growing number of other factors, regulate the induction of beige fat. Three regulators of transcription are central to WAT browning and serve as targets for many of the molecules known to influence this process.[52] These include peroxisome proliferator-activated receptor gamma (PPAR), PR domain containing 16 (PRDM16), and peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1).[52] The list of molecules that influence browning has grown in direct proportion to the popularity of this topic and is constantly evolving as more knowledge is acquired. Among these molecules are irisin and fibroblast growth factor 21 (FGF21), which have been well-studied and are believed to be important regulators of browning. Irisin is secreted from muscle in response to exercise and has been shown to increase browning by acting on beige preadipocytes.[53] FGF21, a hormone secreted mainly by the liver, has garnered a great deal of interest after being identified as a potent stimulator of glucose uptake and a browning regulator through its effects on PGC-1.[43] It is increased in BAT during cold exposure and is thought to aid in resistance to diet-induced obesity[54] FGF21 may also be secreted in response to exercise and a low protein diet, although the latter has not been thoroughly investigated.[55][56] Data from these studies suggest that environmental factors like diet and exercise may be important mediators of browning.

Due to the complex nature of adipose tissue and a growing list of browning regulatory molecules, great potential exists for the use of bioinformatics tools to improve study within this field. Studies of WAT browning have greatly benefited from advances in these techniques, as beige fat is rapidly gaining popularity as a therapeutic target for the treatment of obesity and diabetes.

DNA microarray is a bioinformatics tool used to quantify expression levels of various genes simultaneously, and has been used extensively in the study of adipose tissue. One such study used microarray analysis in conjunction with Ingenuity IPA software to look at changes in WAT and BAT gene expression when mice were exposed to temperatures of 28 and 6C.[57] The most significantly up- and downregulated genes were then identified and used for analysis of differentially expressed pathways. It was discovered that many of the pathways upregulated in WAT after cold exposure are also highly expressed in BAT, such as oxidative phosphorylation, fatty acid metabolism, and pyruvate metabolism.[57] This suggests that some of the adipocytes switched to a beige phenotype at 6C. Mssenbck et al. also used microarray analysis to demonstrate that insulin deficiency inhibits the differentiation of beige adipocytes but does not disturb their capacity for browning.[58] These two studies demonstrate the potential for the use of microarray in the study of WAT browning.

RNA sequencing (RNA-Seq) is a powerful computational tool that allows for the quantification of RNA expression for all genes within a sample. Incorporating RNA-Seq into browning studies is of great value, as it offers better specificity, sensitivity, and a more comprehensive overview of gene expression than other methods. RNA-Seq has been used in both human and mouse studies in an attempt characterize beige adipocytes according to their gene expression profiles and to identify potential therapeutic molecules that may induce the beige phenotype. One such study used RNA-Seq to compare gene expression profiles of WAT from wild-type (WT) mice and those overexpressing Early B-Cell Factor-2 (EBF2). WAT from the transgenic animals exhibited a brown fat gene program and had decreased WAT specific gene expression compared to the WT mice.[59] Thus, EBF2 has been identified as a potential therapeutic molecule to induce beiging.

Chromatin immunoprecipitation with sequencing (ChIP-seq) is a method used to identify protein binding sites on DNA and assess histone modifications. This tool has enabled examination of epigenetic regulation of browning and helps elucidate the mechanisms by which protein-DNA interactions stimulate the differentiation of beige adipocytes. Studies observing the chromatin landscapes of beige adipocytes have found that adipogenesis of these cells results from the formation of cell specific chromatin landscapes, which regulate the transcriptional program and, ultimately, control differentiation. Using ChIP-seq in conjunction with other tools, recent studies have identified over 30 transcriptional and epigenetic factors that influence beige adipocyte development.[59]

The thrifty gene hypothesis (also called the famine hypothesis) states that in some populations the body would be more efficient at retaining fat in times of plenty, thereby endowing greater resistance to starvation in times of food scarcity. This hypothesis, originally advanced in the context of glucose metabolism and insulin resistance, has been discredited by physical anthropologists, physiologists, and the original proponent of the idea himself with respect to that context, although according to its developer it remains "as viable as when [it was] first advanced" in other contexts.[60][61]

In 1995, Jeffrey Friedman, in his residency at the Rockefeller University, together with Rudolph Leibel, Douglas Coleman et al. discovered the protein leptin that the genetically obese mouse lacked.[62][63][64] Leptin is produced in the white adipose tissue and signals to the hypothalamus. When leptin levels drop, the body interprets this as a loss of energy, and hunger increases. Mice lacking this protein eat until they are four times their normal size.

Leptin, however, plays a different role in diet-induced obesity in rodents and humans. Because adipocytes produce leptin, leptin levels are elevated in the obese. However, hunger remains, and- when leptin levels drop due to weight loss- hunger increases. The drop of leptin is better viewed as a starvation signal than the rise of leptin as a satiety signal.[65] However, elevated leptin in obesity is known as leptin resistance. The changes that occur in the hypothalamus to result in leptin resistance in obesity are currently the focus of obesity research.[66]

Gene defects in the leptin gene (ob) are rare in human obesity.[67] As of July, 2010, only 14 individuals from five families have been identified worldwide who carry a mutated ob gene (one of which was the first ever identified cause of genetic obesity in humans)two families of Pakistani origin living in the UK, one family living in Turkey, one in Egypt, and one in Austria[68][69][70][71][72]and two other families have been found that carry a mutated ob receptor.[73][74] Others have been identified as genetically partially deficient in leptin, and, in these individuals, leptin levels on the low end of the normal range can predict obesity.[75]

Several mutations of genes involving the melanocortins (used in brain signaling associated with appetite) and their receptors have also been identified as causing obesity in a larger portion of the population than leptin mutations.[76]

In 2007, researchers isolated the adipose gene, which those researchers hypothesize serves to keep animals lean during times of plenty. In that study, increased adipose gene activity was associated with slimmer animals.[77] Although its discoverers dubbed this gene the adipose gene, it is not a gene responsible for creating adipose tissue.

Pre-adipocytes are undifferentiated fibroblasts that can be stimulated to form adipocytes. Recent studies shed light into potential molecular mechanisms in the fate determination of pre-adipocytes although the exact lineage of adipocyte is still unclear.[78][79]

Adipose tissue has a density of ~0.9g/ml.[80] Thus, a person with more adipose tissue will float more easily than a person of the same weight with more muscular tissue, since muscular tissue has a density of 1.06g/ml.[81]

A body fat meter is a widely available tool used to measure the percentage of fat in the human body. Different meters use various methods to determine the body fat to weight ratio. They tend to under-read body fat percentage.[82]

In contrast with clinical tools, one relatively inexpensive type of body fat meter uses the principle of bioelectrical impedance analysis (BIA) in order to determine an individual's body fat percentage. To achieve this, the meter passes a small, harmless, electric current through the body and measures the resistance, then uses information on the person's weight, height, age, and sex to calculate an approximate value for the person's body fat percentage. The calculation measures the total volume of water in the body (lean tissue and muscle contain a higher percentage of water than fat), and estimates the percentage of fat based on this information. The result can fluctuate several percentage points depending on what has been eaten and how much water has been drunk before the analysis.

Within the fat (adipose) tissue of CCR2 deficient mice, there is an increased number of eosinophils, greater alternative Macrophage activation, and a propensity towards type 2 cytokine expression. Furthermore, this effect was exaggerated when the mice became obese from a high fat diet.[83]

Diagrammatic sectional view of the skin (magnified).

White adipose tissue in paraffin section

Electronic instrument of body fat meter

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Adipose tissue - Wikipedia

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Adipocyte – Wikipedia

Thursday, December 1st, 2016

Adipocytes, also known as lipocytes and fat cells, are the cells that primarily compose adipose tissue, specialized in storing energy as fat.[1]

There are two types of adipose tissue, white adipose tissue (WAT) and brown adipose tissue (BAT), which are also known as white fat and brown fat, respectively, and comprise two types of fat cells. Most recently, the presence of beige adipocytes with a gene expression pattern distinct from either white or brown adipocytes has been described.

White fat cells or monovacuolar cells contain a large lipid droplet surrounded by a layer of cytoplasm. The nucleus is flattened and located on the periphery. A typical fat cell is 0.1mm in diameter with some being twice that size and others half that size. The fat stored is in a semi-liquid state, and is composed primarily of triglycerides and cholesteryl ester. White fat cells secrete many proteins acting as adipokines such as resistin, adiponectin, leptin and apelin. An average human adult has 30 billion fat cells with a weight of 30lbs or 13.5kg. If excess weight is gained as an adult, fat cells increase in size about fourfold before dividing and increasing the absolute number of fat cells present.[2]

Brown fat cells or plurivacuolar cells are polygonal in shape. Unlike white fat cells, these cells have considerable cytoplasm, with lipid droplets scattered throughout. The nucleus is round, and, although eccentrically located, it is not in the periphery of the cell. The brown color comes from the large quantity of mitochondria. Brown fat, also known as "baby fat," is used to generate heat.

Pre-adipocytes are undifferentiated fibroblasts that can be stimulated to form adipocytes. Recent studies shed light into potential molecular mechanisms in the fate determination of pre-adipocytes although the exact lineage of adipocyte is still unclear.[3][4] The variation of body fat distribution resulting from normal growth is influenced by nutritional and hormonal status in dependence on intrinsic differences in cells found in each adipose depot.[5]

Mesenchymal stem cells can differentiate into adipocytes, connective tissue, muscle or bone.[1]

The term "lipoblast" is used to describe the precursor of the adult cell. The term "lipoblastoma" is used to describe a tumor of this cell type.[6]

Even after marked weight loss, the body never loses adipocytes.[citation needed]As a rule, to facilitate changes in weight, the adipocytes in the body merely gain or lose fat content. However, if the adipocytes in the body reach their maximum capacity of fat, they may replicate to allow additional fat storage.

Adult rats of various strains became obese when they were fed a highly palatable diet for several months. Analysis of their adipose tissue morphology revealed increases in both adipocyte size and number in most depots. Reintroduction of an ordinary chow diet[clarification needed] to such animals precipitated a period of weight loss during which only mean adipocyte size returned to normal. Adipocyte number remained at the elevated level achieved during the period of weight gain.[7]

In some reports and textbooks, the number of adipocytes can increase in childhood and adolescence, though the amount is usually constant in adults. Interestingly, individuals who become obese as adults, rather than as adolescents, have no more adipocytes than they had before.[8]

People who have been fat since childhood generally have an inflated number of fat cells. People who become fat as adults may have no more fat cells than their lean peers, but their fat cells are larger. In general, people with an excess of fat cells find it harder to lose weight and keep it off than the obese who simply have enlarged fat cells.[9]

According to research by Tchoukalova et al., 2010, body fat cells could have regional responses to the overfeeding that was studied in adult subjects. In the upper body, an increase of adipocyte size correlated with upper-body fat gain; however, the number of fat cells was not significantly changed. In contrast to the upper body fat cell response, the number of lower-body adipocytes did significantly increase during the course of experiment. Notably, there was no change in the size of the lower-body adipocytes.[10]

Approximately 10% of fat cells are renewed annually at all adult ages and levels of body mass index without a significant increase in the overall number of adipocytes in adulthood.[8]

Obesity is characterized by the expansion of fat mass, through adipocyte size increase (hypertrophy) and, to a lesser extent, cell proliferation (hyperplasia).[11] In the fat cells of obese individuals, there is increased production of metabolism modulators, such as glycerol, hormones, and pro-inflammatory cytokines, leading to the development of insulin resistance.[12]

Fat production in adipocytes is strongly stimulated by insulin. By controlling the activity of the pyruvate dehydrogenase and the acetyl-CoA carboxylase enzymes, insulin promotes unsaturated fatty acid synthesis. It also promotes glucose uptake and induces SREBF1, which activates the transcription of genes that stimulate lipogenesis.[13]

SREBF1 (sterol regulatory element-binding transcription factor 1) is a transcription factor synthesized as an inactive precursor protein inserted into the endoplasmic reticulum (ER) membrane by two membrane-spanning helices. Also anchored in the ER membrane is SCAP (SREBF-cleavage activating protein), which binds SREBF1. The SREBF1-SCAP complex is retained in the ER membrane by INSIG1 (insulin-induced gene 1 protein). When sterol levels are depleted, INSIG1 releases SCAP and the SREBF1-SCAP complex can be sorted into COPII-coated transport vesicles that are exported to the Golgi. In the Golgi, SREBF1 is cleaved and released as a transcriptionally active mature protein. It is then free to translocate to the nucleus and activate the expression of its target genes.

[14]

Clinical studies have repeatedly shown that even though insulin resistance is usually associated with obesity, the membrane phospholipids of the adipocytes of obese patients generally still show an increased degree of fatty acid unsaturation.[15] This seems to point to an adaptive mechanism that allows the adipocyte to maintain its functionality, despite the increased storage demands associated with obesity and insulin resistance.

A study conducted in 2013[15] found that, while INSIG1 and SREBF1 mRNA expression was decreased in the adipose tissue of obese mice and humans, the amount of active SREBF1 was increased in comparison with normal mice and non-obese patients. This downregulation of INSIG1 expression combined with the increase of mature SREBF1 was also correlated with the maintenance of SREBF1-target gene expression. Hence, it appears that, by downregulating INSIG1, there is a resetting of the INSIG1/SREBF1 loop, allowing for the maintenance of active SREBF1 levels. This seems to help compensate for the anti-lipogenic effects of insulin resistance and thus preserve adipocyte fat storage abilities and availability of appropriate levels of fatty acid unsaturation in face of the nutritional pressures of obesity.

Adipocytes can synthesize estrogens from androgens,[16] potentially being the reason why being underweight or overweight are risk factors for infertility.[17] Additionally, adipocytes are responsible for the production of the hormone leptin. Leptin is important in regulation of appetite and acts as a satiety factor.[18]

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Home | The EMBO Journal

Wednesday, October 5th, 2016

Open Access

Article

The Arabidopsis CERK1associated kinase PBL27 connects chitin perception to MAPK activation

These authors contributed equally to this work as first authors

These authors contributed equally to this work as third authors

Chitin receptor CERK1 transmits immune signals to the intracellular MAPK cascade in plants. This occurs via phosphorylation of MAPKKK5 by the CERK1associated kinase PBL27, providing a missing link between pathogen perception and signaling output.

Chitin receptor CERK1 transmits immune signals to the intracellular MAPK cascade in plants. This occurs via phosphorylation of MAPKKK5 by the CERK1associated kinase PBL27, providing a missing link between pathogen perception and signaling output.

CERK1associated kinase PBL27 interacts with MAPKKK5 at the plasma membrane.

Chitin perception induces disassociation of PBL27 and MAPKKK5.

PBL27 functions as a MAPKKK kinase.

Phosphorylation of MAPKKK5 by PBL27 is enhanced upon phosphorylation of PBL27 by CERK1.

Phosphorylation of MAPKKK5 by PBL27 is required for chitininduced MAPK activation in planta.

Kenta Yamada, Koji Yamaguchi, Tomomi Shirakawa, Hirofumi Nakagami, Akira Mine, Kazuya Ishikawa, Masayuki Fujiwara, Mari Narusaka, Yoshihiro Narusaka, Kazuya Ichimura, Yuka Kobayashi, Hidenori Matsui, Yuko Nomura, Mika Nomoto, Yasuomi Tada, Yoichiro Fukao, Tamo Fukamizo, Kenichi Tsuda, Ken Shirasu, Naoto Shibuya, Tsutomu Kawasaki

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Stem cells treatment clinic

Thursday, August 4th, 2016

more than 60 diseases can be treated with stem cells Read More...

Patient from Portugal, Diagnosed Multiple Sclerosis, One month after treatment he could walk again Read More...

Swiss Medica participated in neuro rehabilitation conference march 2015Read More...

NEW modern technology - activating autologous stem cells and replacing damaged cells

Patient from Portugal, 44 years old. Diagnosed Multiple Sclerosis.

In December 2012 his condition exacerbated. He started using wheelchairs. His disease progressed. He was not able to walk. He was not able to see. Nine months of usual treatments for MS accompanied by chemotherapy did not help. Then he found Swiss Medica Stem Cell Clinic. Stem celltreatment started immediately. One month later he was able to walk again.

SEE WHOLE STORY ABOUT J PAUL >>>

Holistic medicine considers a person to be a functional unit. The disease symptoms are signs of disruption in the system of the body. By activating the bodys ability of self-regulation we can eliminate this disruption. In Swiss Medica XXI Century S.A. we seek the cause of the disease, and provide a setting: to allow the body to use its own powers of self-healing to overcome the disease.

Our primary task is to make your own cells treat your own body. We use advanced technology to activate dormant cells (adipose mesenchymal stem cells) to differentiate into the cells we need, and then to replace the damaged cells. Symptoms become less prominent and disappear.

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Stem Cell Facial Fat Transfer in Zionsville, IN

Thursday, August 4th, 2016

As part of a facial fat transfer procedure, physicians are now able incorporate stem cells to help patients achieve the best possible results. Traditional facial fat transfer procedures involve using the patients own body fat to plump up sunken or emaciated areas of the face but the results dont usually last very long. Adult stem cells can be introduced to the process to improve long-term results. Stem cell facial fat transfer procedures are used to treat chronic skin conditions like wrinkles, sun damage and redness.

Stem cells are being used in facial fat transfer procedures because they help stimulate fat cells, which die as we age. When fat cells die, they often cause areas of the face to look sunken, which can cause wrinkles and sagging skin. Stem cells are also believed to encourage cell regeneration, which repairs cells damaged by the sun and aging. Stem cells also stimulate skin cells to produce more collagen and elastin, which thicken and firm skin. Stem cell facial fat transfer procedures are a noninvasive way for patients to reduce natural signs of aging in a natural way.

Adult stem cells are used during fat transfer procedures. These stem cells are different from embryonic stem cells because they are autologous meaning they are extracted from fat in the patients abdomen or thigh. During facial fat transfer procedures, the fat removal and stem cell removal is accomplished at the same time.

Adult stem cells are naturally occurring and regenerative, so the patient is not affected by the removal. Stem cells can be found in various tissues throughout the body and are often referred to as undifferentiated cells meaning they are essentially a biological blank slate. Because of this, stem cells are capable of becoming another differentiated type of cell such as a skin cell, a fat cell or a muscle cell. Stem cells are added to facial fat transfer procedures to improve the quality, health and appearance of the skin over the long term.

A stem cell fat transfer procedure is accomplished in less than an hour, and the patient is given a local anesthetic no general or intravenous anesthesia is necessary. The physician will start by removing the subcutaneous fat from the abdomen or thigh area using a small syringe. Once its harvested, the physician will separate the fat cells, stem cells and growth factor from the fat. This mixture will later be re-injected into the treatment area.

What makes stem cell facial fat transfer procedures different from other fat transfer procedures is that the fat cells and stem cells are mixed with specific combination of growth factors that help them survive. Autologous growth factors such as platelet-rich plasma (PRP) are embedded in micro-hydraulic acid beads to allow for the release of these growth factors over longer periods of time. By constantly stimulating the fat cells and stem cells, growth factors help the damaged tissues develop into healthy tissue.

This anti-aging process ultimately restores lost fat, enhances the volume of the face, and improves the quality and texture of the skin. The procedure usually involves up to three injections of this mixture so that each layer of the skin receives even treatment.

Each patients recovery from a stem cell facial fat transfer procedure will be different depending on the condition being treated. Its important to note that it is not just the face that needs to heal, but the donor site as well. Following the procedure, patients may experience some swelling and bruising around the treatment area during the first seven to 10 days. During this time, patients want to avoid movement in the treatment area to avoid damage to the graft. Minor soreness is expected within the first couple days at the donor site, but it is usually manageable with over-the-counter pain medications.

The effects of this procedure typically last for five to six years. However, with regular care and follow-up appointments to reintroduce growth factors as a way to increase tissue survival, results can last up to eight to 10 years. Results develop over time and are seen during the course of three to four months. Patients have been thrilled with their results because their skin looks and feels better.

Request more information about stem cell facial fat transfer today. Call (317) 900-4440 or contact Dr. Michele Zormeier online.

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Fat Stem Cells Doc. Alberto Rossi Todde

Thursday, August 4th, 2016

Adipose tissue is an inexhaustible source of adult fat stem cells.

Have been identified stem cells capable of producing fat tissue. These fat stem cells from adipose tissue may help to understand how it develops fat tissue and which drugs or develop treatments against obesity. There are two types of adipose tissue: the white adipose tissue (WAT) and brown adipose tissue (BAT), the first one lipid rich while the second one lipids burning and warm producing. BAT founds in adult humans and it is very important to research on obesity because it represents a potential pathway by which the body controls the metabolism burning excess fat to produce heat. Adipose stem cells have many therapeutic Aplications: repair and regeneration of damaged tissues. Can be recovered in large quantities through liposuction or fragments of subcutaneous adipose tissue and can be easily expanded in vitro.

Stem cells have the unique characteristic of being able to choose, with each cell division, whether to produce copies of themselves or specialized cell. Thanks to this characteristic, the stem cells are critical for the maintenance of tissues such as blood, skin and intestines.

The regeneration represents a real alternative: expect the body to repair the damage inflicted by disease, accidents or aging through its stem cells.

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Implications for human adipose-derived stem cells in …

Thursday, August 4th, 2016

Abstract

Adipose-derived stem cells (ADSCs) are a subset of mesenchymal stem cells (MSCs) that possess many of the same regenerative properties as other MSCs. However, the ubiquitous presence of ADSCs and their ease of access in human tissue have led to a burgeoning field of research. The plastic surgeon is uniquely positioned to harness this technology because of the relative frequency in which they perform procedures such as liposuction and autologous fat grafting. This review examines the current landscape of ADSC isolation and identification, summarizes the current applications of ADSCs in the field of plastic surgery, discusses the risks associated with their use, current barriers to universal clinical translatability, and surveys the latest research which may help to overcome these obstacles.

Recent advances in regenerative medicine, in particular the discovery of multipotent, easily accessible stem cells such as adipose-derived stem cells (ADSCs), have provided the opportunity of using autologous stem cell transplants as regenerative therapies. The field of plastic surgery, centred on the restoration and enhancement of the body, is logically positioned to utilize such new technologies focused on the repair and replacement of diseased cells and tissues [1]. The ability of stem cells to self-renew, to secrete trophic factors and to differentiate into different cell types has allowed for the development of more flexible therapies to redefine the classic autologous tissue transplant and offer more customizable treatment options. ADSCs are being utilized for a variety of different applications in plastic surgery [2-11], and as our understanding of the basic science of stem cells continues to develop, the plastic surgeon should be prepared for the translational and clinical implications of this progress.

Adipose-derived stem cells are particularly useful as they can be easily harvested with minimal donor site morbidity and have a differentiation potential similar to other MSCs [12, 13]. In addition, ADSCs have higher yields and greater proliferative rates in culture when compared to bone marrow stromal cells [14-16]. The discovery that ADSCs are not only precursors to adipocytes but also are multipotent progenitors to a variety of cells [17] including osteoblasts, chondrocytes, myocytes, epithelial cells and neuronal cells [18], creates the potential to treat a variety of tissue defects from a single, easily accessible autologous cell source.

Adult stem cell research has made significant strides as a therapeutic modality in recent years. However, there remain significant barriers to the safe and efficacious use of stem cell therapies. With regard to ADSCs, this includes better defining the source population of multipotent cells, optimizing the isolation of these cells in compliance with regulatory standards, and better understanding the behaviour of ADSCs in their transplanted niche. The purpose of this review is to (i) explore the utilization of ADSCs in plastic surgery, (ii) describe the current limitations of ADSC treatments with regard to developing translatable clinical therapies and (iii) describe certain techniques used in our laboratory that may help overcome these barriers. Understanding the current status of clinical ADSC treatments and defining the challenges ahead may bring us closer to achieving desired outcome while minimizing unwanted side effects with these therapies.

The most commonly published method of ADSC isolation involves enzymatic digestion of lipoaspirate to release the stromal vascular fraction (SVF) of cells which include stromal & endothelial cells, pericytes, various white blood cells, red blood cells and stem/progenitor cells [19]. The enzyme preparations used to achieve this fraction include dispase, trypsin and more commonly collagenase. In our laboratory, we take freshly harvested lipoaspirate and wash it with sterile 1% PBS until golden in colour. The adipose tissue is then digested with 0.01% collagenase/PBS solution at a ratio of 1ml of enzyme solution to 1cm3 of adipose tissue. This mixture is incubated at 37C with intermittent agitation until it becomes cloudy (usually 30min.). The infranatant is then carefully aspirated, transferred to 50ml conical tubes and centrifuged at 706g for 8min. The supernatant is discarded and resulting pellet, the SVF, is resuspended in control media [DMEM supplemented with 10% foetal bovine serum (FBS), 500IU penicillin and 500g streptomycin; Mediatech, Manassas, VA, USA]. The cells are then counted and plated in uncoated T75 flasks at a concentration of 1106 cells. Consistently, 20mg of lipoaspirate is ample tissue to harvest an adequate yield of SVF (>1107 cells).

In 2006, the International Society for Cellular Therapy (ICTS) defined a set of minimal criteria for identifying cells as ADSCs. These include plastic adherence while maintained in standard culture conditions, expression of CD73, CD90 and CD105 while lacking the expression of CD45, CD34, CD14 or CD11b, CD79 or CD19 and HLA-DR surface molecules [20]. In conjunction with the International Federation for Adipose Therapeutics and Science in 2013, the ICTS has denoted additional surface markers CD13, CD29 and CD44 as being constitutively expressed at >80% on the surface of ADSCs, while CD31, CD45 and CD235a are the primary negative markers that should be expressed on less than 2% of the cells [19]. Ultimately, the viability of the isolated cells should exceed 70% and the presence of at least two positive and two negative markers are necessary for foundational phenotyping. Finally, ADSCs must possess the ability to differentiate into osteoblasts, adipocytes and chondroblasts.

Identification of ADSCs in our laboratory is accomplished by labelling our plastic-adherent cells with a mesenchymal stem cell (MSC) phenotyping kit after the second passage (Miltenyi Biotec Inc, Auburn, CA, USA). Cells are analysed using a C6 Accuri Flow Cytometer (BD Biosciences, San Jose, CA, USA) which demonstrate positive staining for CD90 (81.3%), CD105 (86.6%) and CD73 (99.9%) and negative staining for CD14, CD20, CD34 and CD45 (1.97% Fig.1). To complete the identification of our ADSCs, we culture these cells in adipogenic, osteogenic, or chondrogenic conditions provided in commercially available kits (Cyagen Biosciences Inc., Sunnyvale, CA, USA). Cells subjected to adipogenic or osteogenic conditions reveal lipid droplets or calcium synthesis after staining with Oil Red O or Alizarin Red S, respectively, after fixation in 4% formalin. Cells subjected to chondrogenic conditions reveal proteoglycan synthesis upon staining with Alcian Blue after paraffin embedding (Fig.2). The ease at which ADSCs can be isolated has led to rapid and widespread translational applications.

Figure1. Flow cytometry analysis of isolated ADSCs after collagenase method. Cells stained (A) 81.3% positive for CD90, (B) 99.9% positive for CD73, (C) 86.6% positive for CD105 and (D) 1.97% positive for CD14, CD20, CD34 and CD45.

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Figure2. Undifferentated and differentiated ADSCs visualized using microscopy. Original magnification, 10. (A) Control stain uADSCs stained with Oil Red O (other controls not shown). (B) Staining with Alcian Blue revealing presence of chondroblasts. (C) Staining with Oil Red O revealing presence of adipocytes. (D) Staining with Alizarin Red S revealing presence of osteoblasts.

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A number of groups have described the isolation of ADSCs using non-enzymatic methods. Studies show that ADSCs reside in the infranatant layer of the suction canister after liposuction and that these cells can be expanded ex vivo. And while these cells exhibit phenotypic and differentiation potential similar to ADSCs isolated via collagenase digestion, their presence is significantly lower with reported yields ranging from a 3- to 19-fold decrease in comparison [21-24]. Interestingly, it has been found that multiple variables, including medical comorbidities of the patient, location adipose tissue stores, and the method in which this tissue is harvested, all affect the properties of the ADSCs therein. For example, diabetic patient fat stores have been found to contain fewer ADSCs with a reduced phenotypic expression profile and ability to proliferate [3]. The anatomical location of adipose tissue harvest also appears to have an effect on the yield and characteristics of the isolated ADSCs [25, 26]. More recently, Gnanasegaran etal. demonstrated that the gene expression levels and tendency towards specific germ layer differentiation is affected by whether the fat is harvested via liposuction versus lipectomy [27].

In Europe, ADSCs are considered Advanced Therapy Medicinal Products, as defined by the European Union (European Commission) 1394/2007 which contains rules for authorization, supervision, and pharmacovigilance regarding the summary of product characteristics, labelling, and packaging of Advanced Therapy Medicinal Products that are prepared commercially and in academic institutions [68]. This regulation refers to the European good manufacturing process (eGMP) rules [69]. The process of converting protocols, including collagenase-processed ADSCs, into a process that is compliant with eGMP requires assays that have had careful consideration of all the risks and benefits for the patient end user. As a result, the general recommendation on the use of enzyme-processed CAL in the clinical setting is not prohibited as this technique has been demonstrated to provide satisfying results in terms of long-term outcome, most likely because of the dramatic release of angiogenic growth factors and the differentiation of ADSCs into adipocytes and vascular endothelial cells [5, 10, 11].

In the United States, the Food and Drug Administration (FDA) regulates Human Cells and Tissue-Based Products (HCT/P) intended for human transplant and maintains two levels of classifications: 361 and 351 products. HCT/P 361 encompasses tissue (e.g. bone, ligaments, vein grafts, etc.) and their related procedures that take place in the same operative session, all of which fall under the jurisdiction of practice of medicine which is governed by state medical boards and professional societies; not the FDA. HCT/P 351, on the other hand, includes drugs/biologics (e.g. cultured cells, lymphocyte immune therapy, cell therapy involving the transfer of genetic material, etc.) which is fully governed by FDA [70, 71]. Regulation 21 CFR 1271 directly demonstrates the FDA's position on enzymatically isolated adipose stem cells derived from SVF for reconstructive purposes as beyond the scope of minimal manipulation and therefore, a drug [72]. Thus, the practical implication is the need for any surgeon who wishes to use ADSCs isolated via collagenase to submit an Investigational New Drug application to the FDA and have an approved Institutional Review Board with the referring Institution.

Given the time, expense and complexity of the regulatory issues surrounding ADSCs intended for transplantation, it is evident that U.S. physicians are discouraged to perform any cell-supplemented lipotransfer techniques in the current commonly accepted practices. Furthermore, automated devices for separating adipose stem cells are regulated as class III medical devices by the FDA, and currently, none are approved for human use in the United States. Kolle etal. demonstrated that CAL, when supplemented with ADSCs expanded ex vivo after collagenase digestion, yields superior results when compared to lipotransfer alone [38]. The FDA restrictions that would preclude such a study to be conducted in the United States prompt an impetus to develop methods for CAL that results in minimal manipulation of source adipose tissue.

In 2006, Yoshimura etal. described a cell population in the liposuction aspirate fluid that exhibited similar phenotypic properties to ADSCs harvested in the traditional manner (collagenase) from processed lipoaspirate cells; however, the yield was reduced by athird when comparing to the two methods [23]. Since that time, additional studies have been published touting the benefits of non-enzymatic ADSC isolation. In 2010, Francis etal. described a method of ADSC Rapid Isolation in ~30min. that excluded the use of collagenase, however, a significant disadvantage of this study was the low yield of ~250,000 cells from a starting volume of ~250ml liposuction aspirate fluid [21]. Zeng etal. describe a rapid and efficient form of non-enzymatic ADSC isolation in which adipose tissue is cut into tiny pieces and placed in culture flasks with 100% FBS in which the plastic-adherent cells were allowed to expand over a period of days [24]. One obvious downside to this method is the requirement to expand the cell population in calf serum. Most recently, Shah etal. describe aform of non-enzymatic ADSC isolation combining the cells of the liposuction aspirate fluid with the cells captured from the processed lipoaspirate tissue wash that is typically discarded prior to collagenase digestion [22]. They observed significant improvement in MSC-related phenotypic markers and similar adipogenic and osteogenic differentiation characteristics. While their isolation time was cut by one-third, they observed a 19-fold decrease in ADSC isolation when compared to the traditional method. In our laboratory, we have adopted a very similar protocol of non-enzymatic isolation that includes processing the processed lipoaspirate effluent. The primary difference in our protocol, however, is the method of plating cells. While Shah etal. plate the entire SVF pellets in T175 flasks, we resuspend our pellets in culture media and then plate the cells at specific concentrations. In one experiment for example, we plated the SVF pellet after collagenase digestion at a concentration of 5105 in a T75 flask. Concurrently, we plated the SVF pellet obtained after non-enzymatic isolation at 2106. After 6days of culture, these two flasks appeared nearly identical in terms of confluence, correlating to a fourfold decrease in ADSC harvest when using the latter method. The two cell populations were then analysed under flow cytometry as previously described. There is little difference in the phenotypic expression between the two populations as demonstrated by >80% expression of CD90, CD73 and CD105 and <5% expression of CD14, CD20, CD 34 and CD45 (Fig.3).

Figure3. Flow cytometry analysis of isolated ADSCs after rapid isolation (no collagenase). Cells stained (A) 85.8% positive for CD90, (B) 99.9% positive for CD73, (C) 99.4% positive for CD105 and (D) 3.79% positive for CD14, CD20, CD34 and CD45. (E) Collagenase-isolated ADSCs after 6days of primary culture seeded at 5105 in T75 flask. (F) Rapid isolation ADSCs after 6days primary culture seeded at 2106 in T75 flask.

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Most convincingly, Kolle etal. demonstrated a clear benefit to CAL over lipotransfer alone. They isolated and expanded ADSCs ex vivo from human cases followed by lipotransfer to the cases arms with or without ADSC supplementation. They demonstrated a 65% improvement in fat graft survival after 4months in the experimental group [38]. The major drawback to their experimental model was that to achieve these results, the 34ml of lipotransfer was supplemented with 6.5108 ADSCs or 2000 times the physiological level [38]. The methods of rapid isolation, previously mentioned, demonstrate the ability to isolate ADSCs without the aid of enzymatic digestion, but at a cost of greatly reduced yields. There is significant doubt that ADSCs used at such low concentrations would serve for any clinical benefit. As previously discussed, ex vivo expansion of ADSCs is not practical for application in the United States or other principalities with strict regulations. Therein lies an impetus to discover innovative methods of ADSC isolation and characterization of the regenerative components of the SVF that might yield similar results to concentrated ADSCs alone.

There is promise in capitalizing on the plastic-adherent properties of ADSCs as a form of non-enzymatic isolation. The same group that first described the isolation of cells from the LAF, Doi etal., has demonstrated that an adherent column of rayonpolyethylene non-woven fabrics may also be used to isolate ADSCs, though at an inferior yield to the traditional method [73]. Further advancements in harnessing the plastic-adherent properties of these cells are clearly needed as Buschmann etal. demonstrated that 3050% of ADSCs remain in suspension after 24hrs of primary culture [74].

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Fat vs. Bone Marrow Stem Cells: A Clinicians Perspective

Thursday, August 4th, 2016

Fat vs. Bone Marrow Stem Cells: A Clinicians Perspective

This week I treated a patient with adipose SVF stem cells to augment a low stem cell yield from bone marrow. I dont do this often, as the quality of fat stem cells for orthopedic applications like arthritis is much less. We do use fat for an occasional structural graft in various procedures. Today I wanted to give you a clinicians eye view of the harvest procedures for both stem cell types that you wont see elsewhere, so let Fat vs Bone Marrow Stem Cells begin.

In summary, harvesting fat in a mini-liposuction is a violent affair, harvesting stem cells from a bone marrow aspirate is like an advanced blood draw. Let me explain.

In order to get fat through a mini-liposuction you need to first use a scalpel to open a small incision in the skin. This isnt at all required for a bone marrow aspiration as the needle is just inserted into the skin like any other needle. In the liposuction, the whole goal is disrupting large amounts of normal tissue. In fact, the stem cells live around the blood vessels, so you have to chew up as many blood vessels in the fat as possible to get a good stem cell yield. This involves placing a small wand like device under the skin and into the fat and moving it back and forth (through much resistance) to break apart large sections of tissue. The bone marrow aspiration simply involves directing the needle under the x-ray to the desired area of bone. The needle is then turned back and forth a few times to enter the bone (which is like hard plastic instead of cement). At this point in the liposuction the doctor must continue to break up large swaths of tissue with suction, sucking the broken tissue and blood vessels into a syringe. On the other hand, in the bone marrow aspiration the doctor simply draws the bone marrow aspirate (which looks like blood) into the syringe like a common blood draw.

The complication rates for these two procedures tell the rest of the story. Mini-liposuction procedures have surgical style complication rates of 3-10%, while bone marrow aspiration complication rates are so rare that only a handful occurred in more than 20,000 procedures in one U.K. registry. The upshot? It always makes me chuckle (in a bad way) when I hear fat stem cell advocates claim that a bone marrow aspiration procedure is so invasive. Youhavent seen invasive until youve seen a lipo-suction!

Disclaimer: Like all medical procedures, Regenexx Procedures have a success & failure rate. Not all patients will experience the same results.

If you liked this post, you may really enjoy this book by the same author - Dr. Chris Centeno

Written by Regenexx Founder, Dr. Chris Centeno, this 150 page book explains the Regenexx approach to patients and orthopedic conditions. Whether youre are an existing patient or simply interested in the human body and how everything in the body ties together, you will enjoy exploring this book in-depth. With hyperlinks to more detailed information, related studies and commentary, this book condenses a huge amount of data and resources into an enjoyable and entertaining read.

Chris Centeno, M.D. is a specialist in regenerative medicine and the new field of Interventional Orthopedics. Centeno pioneered orthopedic stem cell procedures in 2005 and is responsible for a large amount of the published research on stem cell use for orthopedic applications. Centeno regularly lectures on regenerative medicine and has spoken twice at the Vatican Stem Cell Conference.

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High-fat diets may spur cancer by activating tumor-prone …

Thursday, August 4th, 2016

Chowing down on a high-fat diet may not only grow your waistline. It may also plump stem cell populations in your gutcells that are prone to producing tumors.

After about a year of feeding mice a diet of 60 percent fat, researchers found that the rodents had an unusually hefty population of cancer-susceptible intestinal stem cells and cells that act like stem cells. Those cells were supercharged by a protein called PPAR-, which can be switched on by the presence of fatty acids in the gut, the researchers reported.

The findings, published in Nature, may explain why epidemiological data in humans has repeatedly linked obesity to boosted risks of cancer, particularly colon cancer. It may also offer researchers a new target for knocking back the risks of cancer in the obese.

In the gut, there is usually a tiny pocket of stem cells that works to replenish the cells that line the intestine. These cells hang around for a lifetime, giving them extra opportunities to acquire mutations that could spur tumors.

In the fat-fed mice, which grew chubby, this tiny stem cell population unexpectedly flourished. And, progenitor cellsspecialized progeny of stem cellsstarted acting more like their parents, too. They lived longer, upping their opportunities to acquire mutations and tumor-spawning potential.

The researchers found that PPAR- was behind that boom in stem and progenitor cells. In petri-dish experiments, the researchers found that fatty acids from the high-fat diet increased the amounts of PPAR- cells were making.

That makes sense because the protein is known to switch on metabolic machinery that helps burn fat over carbohydrates. But the protein also seems to spark specific genetic changes that ignite the two cell populations, the researchers suggest.

In their fat mice, the researchers noted higher rates of spontaneous tumors than in control mice.

Still, the researchers will need to do more work to know if PPAR- and the stem cells explain the link between cancer and obesity in humans.

Nature, 2015. DOI: 10.1038/nature.2016.19484 (About DOIs).

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What are Stem Cells? – University of Nebraska Medical Center

Thursday, August 4th, 2016

What are Stem Cells?

Types of Stem Cells

Why are Stem Cells Important?

Can doctors use stem cells to treat patients?

Pros and Cons of Using Stem Cells

What are Stem Cells?

There are several different types of stem cells produced and maintained in our system throughout life. Depending on the circumstances and life cycle stages, these cells have different properties and functions. There are even stem cells that have been created in the laboratory that can help us learn more about how stem cells differentiate and function. A few key things to remember about stem cells before we venture into more detail:

Stem cells are the foundation cells for every organ and tissue in our bodies. The highly specialized cells that make up these tissues originally came from an initial pool of stem cells formed shortly after fertilization. Throughout our lives, we continue to rely on stem cells to replace injured tissues and cells that are lost every day, such as those in our skin, hair, blood and the lining of our gut.

Source ISSCR

Stem Cell History

Until recently, scientists primarily worked with two kinds of stem cells from animals and humans: embryonic stem cells and non-embryonic "somatic" or "adult" stem cells. Scientists discovered ways to derive embryonic stem cells from early mouse embryos nearly 30 years ago, in 1981. The detailed study of the biology of mouse stem cells led to the discovery, in 1998, of a method to derive stem cells from human embryos and grow the cells in the laboratory. These cells are called human embryonic stem cells. The embryos used in these studies were created for reproductive purposes through in vitro fertilization procedures. When they were no longer needed for that purpose, they were donated for research with the informed consent of the donor. In 2006, researchers made another breakthrough by identifying conditions that would allow some specialized adult cells to be "reprogrammed" genetically to assume a stem cell-like state. This new type of stem cell is now known as induced pluripotent stem cells (iPSCs).

Source NIH

Types of Stem Cells

Adult Stem Cells (ASCs):

ASCs are undifferentiated cells found living within specific differentiated tissues in our bodies that can renew themselves or generate new cells that can replenish dead or damaged tissue. You may also see the term somatic stem cell used to refer to adult stem cells. The term somatic refers to non-reproductive cells in the body (eggs or sperm). ASCs are typically scarce in native tissues which have rendered them difficult to study and extract for research purposes.

Resident in most tissues of the human body, discrete populations of ASCs generate cells to replace those that are lost through normal repair, disease, or injury. ASCs are found throughout ones lifetime in tissues such as the umbilical cord, placenta, bone marrow, muscle, brain, fat tissue, skin, gut, etc. The first ASCs were extracted and used for blood production in 1948. This procedure was expanded in 1968 when the first adult bone marrow cells were used in clinical therapies for blood disease.

Studies proving the specificity of developing ASCs are controversial; some showing that ASCs can only generate the cell types of their resident tissue whereas others have shown that ASCs may be able to generate other tissue types than those they reside in. More studies are necessary to confirm the dispute.

Types of Adult Stem Cells

Embryonic Stem Cells (ESCs):

During days 3-5 following fertilization and prior to implantation, the embryo (at this stage, called a blastocyst), contains an inner cell mass that is capable of generating all the specialized tissues that make up the human body. ESCs are derived from the inner cell mass of an embryo that has been fertilized in vitro and donated for research purposes following informed consent. ESCs are not derived from eggs fertilized in a womans body.

These pluripotent stem cells have the potential to become almost any cell type and are only found during the first stages of development. Scientists hope to understand how these cells differentiate during development. As we begin to understand these developmental processes we may be able to apply them to stem cells grown in vitro and potentially regrow cells such as nerve, skin, intestine, liver, etc for transplantation.

Induced Pluripotent Stem Cells (iPSCs)

Induced pluripotent stem cells are stem cells that are created in the laboratory, a happy medium between adult stem cells and embryonic stem cells. iPSCs are created through the introduction of embryonic genes into a somatic cell (a skin cell for example) that cause it to revert back to a stem cell like state. These cells, like ESCs are considered pluripotent Discovered in 2007, this method of genetic reprogramming to create embryonic like cells, is novel and needs many more years of research before use in clinical therapies.

NIH

Why are Stem Cells Important?

Stem cells are important for living organisms for many reasons. In the 3- to 5-day-old embryo, called a blastocyst, the inner cells give rise to the entire body of the organism, including all of the many specialized cell types and organs such as the heart, lung, skin, sperm, eggs and other tissues. In some adult tissues, such as bone marrow, muscle, and brain, discrete populations of adult stem cells generate replacements for cells that are lost through normal wear and tear, injury, or disease.

Given their unique regenerative abilities, stem cells offer new potentials for treating diseases such as diabetes, and heart disease. However, much work remains to be done in the laboratory and the clinic to understand how to use these cells for cell-based therapies to treat disease, which is also referred to as regenerative or reparative medicine.

Laboratory studies of stem cells enable scientists to learn about the cells essential properties and what makes them different from specialized cell types. Scientists are already using stem cells in the laboratory to screen new drugs and to develop model systems to study normal growth and identify the causes of birth defects.

Research on stem cells continues to advance knowledge about how an organism develops from a single cell and how healthy cells replace damaged cells in adult organisms. Stem cell research is one of the most fascinating areas of contemporary biology, but, as with many expanding fields of scientific inquiry, research on stem cells raises scientific questions as rapidly as it generates new discoveries.

Source NIH

Can doctors use stem cells to treat patients?

Some stem cells, such as the adult bone marrow or peripheral blood stem cells, have been used in clinical therapies for over 40 years. Other therapies utilizing stem cells include skin replacement from adult stem cells harvested from hair follicles that have been grown in culture to produce skin grafts. Other clinical trials for neuronal damage/disease have also been conducted using neural stem cells. There were side effects accompanying these studies and further investigation is warranted. Although there is much research to be conducted in the future, these studies give us hope for the future of therapeutics with stem cell research.

Potential Therapies using Stem Cells

Adult Stem Cell Therapies

Bone marrow and peripheral blood stem cell transplants have been utilized for over 40 years as therapy for blood disorders such as leukemia and lymphoma, amongst many others. Scientists have also shown that stem cells reside in most tissues of the body and research continues to learn how to identify, extract, and proliferate these cells for further use in therapy. Scientists hope to yield therapies for diseases such as type I diabetes and repair of heart muscle following heart attack.

Scientists have also shown that there is potential in reprogramming ASCs to cause them to transdifferentiate (turn back into a different cell type than the resident tissue it was replenishing).

Embryonic Stem Cell (ESC) Therapies

There is potential with ESCs to treat certain diseases in the future. Scientists continue to learn how ESCs differentiate and once this method is better understood, the hope is to apply the knowledge to get ESCs to differentiate into the cell of choice that is needed for patient therapy. Diseases that are being targeted with ESC therapy include diabetes, spinal cord injury, muscular dystrophy, heart disease, and vision/hearing loss.

Induced Pluripotent Stem Cell Therapies

Therapies using iPSCs are exciting because somatic cells of the recipient can be reprogrammed to en ESC like state. Then mechanisms to differentiate these cells may be applied to generate the cells in need. This is appealing to clinicians because this avoids the issue of histocompatibility and lifelong immunosuppression, which is needed if transplants use donor stem cells.

iPS cells mimic most ESC properties in that they are pluripotent cells, but do not currently carry the ethical baggage of ESC research and use because iPS cells have not been able to be manipulated to grow the outer layer of an embryonic cell required for the development of the cell into a human being.

Pros and Cons of Using Various Stem Cells

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What are adult stem cells? [Stem Cell Information]

Thursday, August 4th, 2016

An adult stem cell is thought to be an undifferentiated cell, found among differentiated cells in a tissue or organ. The adult stem cell can renew itself and can differentiate to yield some or all of the major specialized cell types of the tissue or organ. The primary roles of adult stem cells in a living organism are to maintain and repair the tissue in which they are found. Scientists also use the term somatic stem cell instead of adult stem cell, where somatic refers to cells of the body (not the germ cells, sperm or eggs). Unlike embryonic stem cells, which are defined by their origin (cells from the preimplantation-stage embryo), the origin of adult stem cells in some mature tissues is still under investigation.

Research on adult stem cells has generated a great deal of excitement. Scientists have found adult stem cells in many more tissues than they once thought possible. This finding has led researchers and clinicians to ask whether adult stem cells could be used for transplants. In fact, adult hematopoietic, or blood-forming, stem cells from bone marrow have been used in transplants for more than 40 years. Scientists now have evidence that stem cells exist in the brain and the heart, two locations where adult stem cells were not at firstexpected to reside. If the differentiation of adult stem cells can be controlled in the laboratory, these cells may become the basis of transplantation-based therapies.

The history of research on adult stem cells began more than 60 years ago. In the 1950s, researchers discovered that the bone marrow contains at least two kinds of stem cells. One population, called hematopoietic stem cells, forms all the types of blood cells in the body. A second population, called bone marrow stromal stem cells (also called mesenchymal stem cells, or skeletal stem cells by some), were discovered a few years later. These non-hematopoietic stem cells make up a small proportion of the stromal cell population in the bone marrow and can generate bone, cartilage, and fat cells that support the formation of blood and fibrous connective tissue.

In the 1960s, scientists who were studying rats discovered two regions of the brain that contained dividing cells that ultimately become nerve cells. Despite these reports, most scientists believed that the adult brain could not generate new nerve cells. It was not until the 1990s that scientists agreed that the adult brain does contain stem cells that are able to generate the brain's three major cell typesastrocytes and oligodendrocytes, which are non-neuronal cells, and neurons, or nerve cells.

Adult stem cells have been identified in many organs and tissues, including brain, bone marrow, peripheral blood, blood vessels, skeletal muscle, skin, teeth, heart, gut, liver, ovarian epithelium, and testis. They are thought to reside in a specific area of each tissue (called a "stem cell niche"). In many tissues, current evidence suggests that some types of stem cells are pericytes, cells that compose the outermost layer of small blood vessels. Stem cells may remain quiescent (non-dividing) for long periods of time until they are activated by a normal need for more cells to maintain tissues, or by disease or tissue injury.

Typically, there is a very small number of stem cells in each tissue and, once removed from the body, their capacity to divide is limited, making generation of large quantities of stem cells difficult. Scientists in many laboratories are trying to find better ways to grow large quantities of adult stem cells in cell culture and to manipulate them to generate specific cell types so they can be used to treat injury or disease. Some examples of potential treatments include regenerating bone using cells derived from bone marrow stroma, developing insulin-producing cells for type1 diabetes, and repairing damaged heart muscle following a heart attack with cardiac muscle cells.

Scientists often use one or more of the following methods to identify adult stem cells: (1) label the cells in a living tissue with molecular markers and then determine the specialized cell types they generate; (2) remove the cells from a living animal, label them in cell culture, and transplant them back into another animal to determine whether the cells replace (or "repopulate") their tissue of origin.

Importantly, scientists must demonstrate that a single adult stem cell can generate a line of genetically identical cells that then gives rise to all the appropriate differentiated cell types of the tissue. To confirm experimentally that a putative adult stem cell is indeed a stem cell, scientists tend to show either that the cell can give rise to these genetically identical cells in culture, and/or that a purified population of these candidate stem cells can repopulate or reform the tissue after transplant into an animal.

As indicated above, scientists have reported that adult stem cells occur in many tissues and that they enter normal differentiation pathways to form the specialized cell types of the tissue in which they reside.

Normal differentiation pathways of adult stem cells. In a living animal, adult stem cells are available to divide for a long period, when needed, and can give rise to mature cell types that have characteristic shapes and specialized structures and functions of a particular tissue. The following are examples of differentiation pathways of adult stem cells (Figure 2) that have been demonstrated in vitro or in vivo.

Figure 2. Hematopoietic and stromal stem cell differentiation. Click here for larger image. ( 2008 Terese Winslow)

Transdifferentiation. A number of experiments have reported that certain adult stem cell types can differentiate into cell types seen in organs or tissues other than those expected from the cells' predicted lineage (i.e., brain stem cells that differentiate into blood cells or blood-forming cells that differentiate into cardiac muscle cells, and so forth). This reported phenomenon is called transdifferentiation.

Although isolated instances of transdifferentiation have been observed in some vertebrate species, whether this phenomenon actually occurs in humans is under debate by the scientific community. Instead of transdifferentiation, the observed instances may involve fusion of a donor cell with a recipient cell. Another possibility is that transplanted stem cells are secreting factors that encourage the recipient's own stem cells to begin the repair process. Even when transdifferentiation has been detected, only a very small percentage of cells undergo the process.

In a variation of transdifferentiation experiments, scientists have recently demonstrated that certain adult cell types can be "reprogrammed" into other cell types in vivo using a well-controlled process of genetic modification (see Section VI for a discussion of the principles of reprogramming). This strategy may offer a way to reprogram available cells into other cell types that have been lost or damaged due to disease. For example, one recent experiment shows how pancreatic beta cells, the insulin-producing cells that are lost or damaged in diabetes, could possibly be created by reprogramming other pancreatic cells. By "re-starting" expression of three critical beta cell genes in differentiated adult pancreatic exocrine cells, researchers were able to create beta cell-like cells that can secrete insulin. The reprogrammed cells were similar to beta cells in appearance, size, and shape; expressed genes characteristic of beta cells; and were able to partially restore blood sugar regulation in mice whose own beta cells had been chemically destroyed. While not transdifferentiation by definition, this method for reprogramming adult cells may be used as a model for directly reprogramming other adult cell types.

In addition to reprogramming cells to become a specific cell type, it is now possible to reprogram adult somatic cells to become like embryonic stem cells (induced pluripotent stem cells, iPSCs) through the introduction of embryonic genes. Thus, a source of cells can be generated that are specific to the donor, thereby increasing the chance of compatibility if such cells were to be used for tissue regeneration. However, like embryonic stem cells, determination of the methods by which iPSCs can be completely and reproducibly committed to appropriate cell lineages is still under investigation.

Many important questions about adult stem cells remain to be answered. They include:

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What are adult stem cells? [Stem Cell Information]

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Exercise boosts health by influencing stem cells to become …

Thursday, August 4th, 2016

McMaster researchers have found one more reason to exercise: working out triggers influential stem cells to become bone instead of fat, improving overall health by boosting the body's capacity to make blood.

The body's mesenchymal stem cells are most likely to become fat or bone, depending on which path they follow.

Using treadmill-conditioned mice, a team led by the Department of Kinesiology's Gianni Parise has shown that aerobic exercise triggers those cells to become bone more often than fat.

The exercising mice ran less than an hour, three times a week, enough time to have a significant impact on their blood production, says Parise, an associate professor.

In sedentary mice, the same stem cells were more likely to become fat, impairing blood production in the marrow cavities of bones.

The research appears in a new paper published by the Journal of the Federation of American Societies for Experimental Biology.

"The interesting thing was that a modest exercise program was able to significantly increase blood cells in the marrow and in circulation," says Parise. "What we're suggesting is that exercise is a potent stimulus -- enough of a stimulus to actually trigger a switch in these mesenchymal stem cells."

The composition of cells in the bone marrow cavity has an important influence on the productivity of blood stem cells.

In ideal conditions, blood stem cells create healthy blood that boosts the immune system, permits the efficient uptake of oxygen, and improves the ability to clot wounds.

Bone cells improve the climate for blood stem cells to make blood.

But when fat cells start to fill the bone marrow cavity -- a common symptom of sedentary behavior -- blood stem cells become less productive, and conditions such as anemia can result.

The findings add to the growing list of established benefits of exercise, Parise says, and suggest that novel non-medicinal treatments for blood-related disorders may be in the future.

"Some of the impact of exercise is comparable to what we see with pharmaceutical intervention," he says. "Exercise has the ability to impact stem cell biology. It has the ability to influence how they differentiate."

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New source of fat tissue stem cells discovered — ScienceDaily

Thursday, August 4th, 2016

Researchers have found a new source of stem cells that produce fat tissue, findings presented today at the European Congress of Endocrinology in Wrocaw, Poland, show. This unique in vitro human stem cell model of brown fat tissue could aid studies into how fat tissue develops and the development of new anti-obesity drugs.

There are two types of fat tissue found in humans: white adipose tissue (WAT) that accumulates lipids, and brown adipose tissue (BAT) that can burn lipids to produce heat. BAT is mainly found in babies, although recent studies show that adults may retain a small amount of BAT. BAT is considered important in obesity research as it represents a potential pathway by which the body can control metabolism by burning excess lipids to produce heat. Previously there have been no in vitro human models to aid research into BAT tissue development.

A team from the University of Florence in Italy studied patients with a rare tumor called pheochromocytoma. This tumor is found in the adrenal glands and causes the release of excess levels of the hormones adrenaline and noradrenaline. The team removed tumors from eight patients and examined the fat tissue that surrounded them. They found that, in addition to the WAT present in healthy people, pheochromocytoma patients also had some tissue with molecular markers for BAT cells present.

From this tissue, the team isolated and characterized brown adipose stem cells and compared their properties to precursor WAT cells from the same patient. Using gene expression analysis, immunophenotyping and differentiation tools, they found the two cell types had different properties, in particular in their potential to differentiate into BAT cells, thus indicating a different developmental pathway for the two types of fat cell.

This is an exciting discovery, said Professor Michaela Luconi, who led the research. Obesity is now a huge, worldwide health issue and we urgently need new treatment strategies to tackle it. Brown adipose tissue has long been seen as a potential target for new anti-obesity treatments as it is able to control metabolic rate and burn excess fat molecules.

Our research has characterized the first in vitro human model for brown adipose stem cells from a novel source. Our theory is that the excess adrenaline produced by this rare tumor may have induced the expansion of the brown adipose stem cell component present in this depot of white adipose tissue. We now need to carry out further work to see if this theory is correct and whether the process can be reproduced in the lab.

The team are currently unable to produce mature BAT cells from the brown adipose stem cells, but now plan to study how they can improve this differentiation process. This model has huge potential to allow us to learn more about how different types of fat cell develop, said Professor Luconi. Greater understanding of this process will aid us in designing and testing specific anti-obesity drugs targeting white to brown cells conversion.

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Fat Stem Cells – Center For SmartLipo & Plastic Surgery

Thursday, August 4th, 2016

Body fat contains regenerative stem cells that have the ability to revitalize and heal. A leader in the cosmetic enhancement field, the Center for Smart Lipo and Plastic Surgery in Langhorne, PA now offers fat transfer procedures that utilize stem cells. Patients achieve impressive results in body contouring and facial rejuvenation through the use of their own fat cells. Dr. Richard Goldfarb, an experienced and certified doctor at the facility, participates in ongoing research regarding the use of stem cells for cosmetic and non-cosmetic purposes.

About Stem Cells from Fat The web is filled with stories and articles about professional sports figures who have healed their injuries with fat-derived stem cells. Globally, many people are having fat taken from their bodies and using the stem cells within it to aid with different medical issues, such as wounds and muscular difficulties. The stem cells produced in fat are not the same as those found in embroyos, which is considered to be controversial. The adult body produces these cells in fat and also the bone marrow. They are very easy and inexpensive to harvest for medical purposes, without troubling ethical considerations.

Benefits of Fat Stem Cells Stem cells from fat can be used in several cosmetic procedures, such as augmentation of the buttocks and the breasts. It is also used to enhance the facial features, by smoothing out fine lines and wrinkles. The largest benefit to using fat is that it offers superior results over other methods. Using a persons own fat also increases its survival rate, which will help the results to last over the long term.

Anyone who is interested in receiving a fat stem cell cosmetic procedure should contact the experienced staff at the Center for Smart Lipo and Plastic Surgery for more information and a consultation.

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Breast cancer has a higher incidence in obese women …

Thursday, August 4th, 2016

An international team of researchers, with the participation of the University of Granada (UGR), has revealed new data on why breast cancer has a higher incidence and is more aggressive in obese people. The reason is that peritumoral fat (the fat around the tumor) facilitates the expansion and invasion of cancer stem cells (CSCs), which are responsible of the onset and growth of the tumor.

CSCs are found in tumors in a very small proportion, and their main characteristic is that they are responsible of metastasis originating in parts of the body far from the original tumor. Conventional chemotherapy and radiotherapy treatments are not capable of eliminating said CSCs, and for that, it's very common that, after the first response to the treatment, many cancer patients suffer a relapse.

This new research work has been lead by the University of Miami (Florida, United States), and it has counted with the participation of researchers from Granada's University Hospital Center and from the UGR "Terapias avanzadas: diferenciacin, regeneracin y cncer" (Advanced therapies: differentiation, regeneration and cancer) research team. Both groups of researchers belong to the Biosanitary Institute of Granada (ibs. GRANADA).

Mechanisms yet to be clarified

The consequences of the obesity epidemic on cancer morbidity and mortality are very serious. In fact, it is estimated that, nowadays, up to 20% of cancer-related deaths may be attributable to obesity.

Obese women have a greater risk of suffering breast cancer after menopause, and they have a worse progression of the disease no matter their age, but the mechanisms by which obesity contributes to the development and progression of cancer aren't clear yet. Obesity-related fat causes local inflammation and prevents adipocytes (the cells forming said fat) from maturing.

For this research, carried out in mice and published in the journal Cancer Research, researchers assessed the effects of coculturing adipocytes with breast cancer cells on tumor aggressivity, capacity of local invasion and metastatic potential of said tumor.

The results show that the interaction between tumor cells and immature adipocytes near the tumor during the first stages of breast cancer increased the secretion of cytokines (proinflammatory proteins).

"Said cytokines cause a greater expansion of highly metastatic CSCs," UGR professor Juan Antonio Marchal Corrales, one of the authors of this paper, explains.

Preclinical rationale

In addition, the researchers have described the mechanism by which this process takes place and its relation with the activation of the SRC Kinase protein. In turn, said protein induces the activation of the Sox2 transcription factor (essential to maintain stem cells characteristics) and of a small RNA molecule called miRNA-302b.

"The prolonged coculture of tumor cells with immature adipocytes or cytokines increased the proportion of CSCs (which had the ability to form new tumors), the presence of tumor cells in blood, and the metastatic potential after its implementation in mice -Marchal says-. And last, we found that SRC-Kinase-inhibiting drugs decrease the production of cytokines and CSCs."

These findings reveal new insights underlying increased breast cancer mortality in obese individuals and provide a novel preclinical rationale to test the efficacy of SRC inhibitors for breast cancer treatment.

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Extracting stem cells from fat for tissue regeneration …

Thursday, August 4th, 2016

Stem cells extracted from body fat may pave the way for the development of new regenerative therapies including soft tissue reconstruction following tumor removal or breast mastectomy surgery, the development of tissue-engineered cartilage or bone, and the treatment of cardiovascular disease.

An interdisciplinary team of Queen's University researchers led by Dr. Lauren Flynn, a professor in the Departments of Chemical Engineering and Anatomy and Cell Biology, has been working with stem cells extracted from samples of human fat and is developing new methods in the lab to develop these cells into mature tissue substitutes.

While stem cells extracted from fat cannot be grown into as many different types of cells as embryonic stem cells, they do have a number of advantages.

"The advantages include less ethical controversy, abundant cell availability from discarded tissues from elective surgeries like breast reductions and tummy tucks, and a much reduced possibility for immune rejection when re-implanting cells extracted from a person's own fat," explains Dr. Juares Bianco, a postdoctoral fellow in the Department of Chemical Engineering and the Human Mobility Research Centre (HMRC) who is working in the Flynn lab group.

Sarah Fleming, a Master's candidate in the group, is also working to establish a new method for growing the fat stem cells in the lab using a system that mimics the natural tissue environment found within the body. This work is based on Dr. Flynn's development of a technique for washing away all traces of cells from a sample of body fat, leaving behind a three-dimensional tissue scaffold that she calls "decellularized adipose tissue," or "DAT" for short.

This empty scaffold can then be used for soft tissue reconstruction or as a growing environment for the extracted stem cells. Dr. Flynn's preliminary studies have shown that when the stem cells are grown on the DAT scaffold, they naturally begin to mature into fat cells, suggesting that the engineered growth environment influences the type of cell that the basic stem cells will turn into during the tissue regeneration process.

This research was funded in part by NSERC's Collaborative Research and Training Experience Program (CREATE) and was conducted by researchers in the Human Mobility Research Centre (HMRC). The HMRC is a partnership between Queen's University and Kingston General Hospital and serves as a point of collaboration between the disciplines of medicine, engineering, health sciences, and information technology.

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About Adipose Stem Cell Therapy

Thursday, August 4th, 2016

Adipose Stem Cell Therapy

What is an Autologous Adipose Stem Cell Procedure?

A small sample of Adipose tissue (fat) is removed from above the Superior Iliac spine (love handles) or abdomen under a local anesthetic.

Obtaining Adipose-Derived Stem Cells (ADSCs) is much easier and less invasive than performing abone marrowextraction. In addition, adipose tissue contains much larger volumes of mesenchymal stem cells than does bone marrow. We use the patient's own adipose tissue to extract the stem cells. Autologous meansthat the donor and the recipient are the same person.

Benefits of ADSCs: Stem cells play an integral part in wound healing and regeneration of tissue at the cellular level.

The Major Advantages of Adipose Stem Cell Therapy:

Is this procedure a significant improvement on other treatments currently available?

Yes We can now obtain Adult Stem Cells (ASCs) from a fat sample. This in-clinic treatment is completed the same day, and there is no need to ship samples to an outside laboratory and wait days for the cells to be returned for an injection on a second visit. This faster process provides increased stem cell counts, without manipulation.

Is an Autologous Adipose Stem Cell Procedure Safe?

Yes because the adipose tissue is removed from one's own body via sterile technique and remains in a controlled environment there are no problems with cell rejection or disease transmission. The interview, physical, harvesting, and administration of stem cells are all performed in-house under a physicians control.

How do I know if stem cell therapy is right for me?

Discussing treatment options with your physician is an important first step in making a decision regarding stem cell therapy. Potential outcomes, an integrative and comprehensive treatment plan, and financial costs are all factors to consider.

I have heard Stem Cell Treatments are VERY expensive, can I afford this?

Yes you can!

Due to our advanced adult stem cell technology provided in the form of an in house procedure, our Stem Cell Center can now provide this service at a fraction of the cost previously incurred. Even better, its a same day procedure.We offer theentirety of our treatment in Phoenix, Arizona -USA and we have been able to lower our cost to a flat rate of $7,100.00 per treatment (including consultation). Fees are subject to change and some more complex proceduresmay incur additional costs.

Why Choose an Adipose Stem Cell Procedure?

Adipose-derived mesenchymal stem cells areeasier to harvest than bone marrowand can be obtained in much larger quantities. In addition, it is much less painful and involves lower risks.

*There is a much shorter time from extraction to the administration oftreatment.No culturing or manipulation is needed using our procedure, as opposed to a bone marrow extraction which requires days or weeksto reach the necessary therapeutic threshold.

*There are no ethical or moral issues involved in harvesting autologous Adult Stem Cells (ASCs).

Are There Detrimental Side Effects from an Adipose Stem Cell Procedure?

No, the adipose tissue is extracted from the patients own body sono foreign donors are used. This minimizes the potential for immune rejection.Our procedure is performed completely in-house and administered by licensed physicians here in the United States. Please keep in mind that every procedure does have its risks, but we do practice sterile technique which makes the risk of infectionvery low.In fact, we have not had any infections develop in any of the stem cell patients we have treated as we take great care in keeping a sterile environment.

What You Can Expect When Visiting the Stem Cell Rejuvenation Center:

Differences Between An Adipose And A Bone Marrow Procedure:

Autologous Growth Factor Components of PRP:

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New stem cell treatment using fat cells … – ScienceAlert

Thursday, August 4th, 2016

In a world first, Australian scientists have figured out how to reprogram adult bone or fat cells to form stem cells that could potentially regenerate any damaged tissue in the body.

The researchers were inspired by the way salamanders are able to replace lost limbs, and developed a technique that gives adult cells the ability to lose their adultcharacteristics, multiply and regenerate multiple cell types - what is known as multipotency.That means the new stem cells can hypothetically repairany injury in the body, from severed spinal cords to joint and muscle degeneration. And its a pretty big deal, because there are currently no adult stem cells that naturally regenerate multiple tissue types.

"This technique is a significant advance on many of the current unproven stem cell therapies, which have shown little or no objective evidence they contribute directly to new tissue formation," said lead researcher John Pimanda from the University of New South Wales, Faculty of Medicine (UNSW Medicine). "We are currently assessing whether adult human fat cells reprogrammed into [induced multipotent stem cells (iMS cells)] can safely repair damaged tissue in mice, with human trials expected to begin in late 2017."

Right now, although its an exciting and much-hyped field of study, stem cell therapy still has a number of limitations, primarily because the most useful cells are embryonic stem cells, which are taken from developing embryos and have the potential to become any cell type in the body.But they also have the tendency to form tumours and cannot be transplanted directly to regenerate adult cells.

Instead, researchers are able to use tissue-specific adult cells, which can only turn into the cell types in their region of the body for example, lung stem cells can only differentiate into lung tissue, so theyre not as versatile as scientists need.

Scientists have also worked out how to reprogram regular adult stem cells into induced pluripotent stem cells (iPS) a type of stem cell thats even more flexible than multipotent stem cells, but requires the use of viruses in order for the cells to be reset, which isnt ideal to help treat patients. Thats why the new research is so exciting.

"Embryonic stem cells cannot be used to treat damaged tissues because of their tumour forming capacity," said one of the researchers, Vashe Chandrakanthan. "The other problem when generating stem cells is the requirement to use viruses to transform cells into stem cells, which is clinically unacceptable."

"We believe weve overcome these issues with this new technique."

To create the new type of stem cells, the researchers collected adult human bone and fat cells and treated them with two compounds: 5-Azacytidine (AZA); and platelet-derived growth factor-AB (PDGF-AB) for two days.

This kick-started the process of dedifferentiation which basically means it started to revert them to a multipotent stem cell state. The cells were then kept in PDGF-AB for a few weeks while they slowly changed into stem cells, eventually becoming tissue-regenerative iMS cells which basically means they can repair any type of tissue in the body.

"This technique is ground-breaking because iMS cells regenerate multiple tissue types," said Pimanda. "We have taken bone and fat cells, switched off their memory and converted them into stem cells so they can repair different cell types once they are put back inside the body."

Right now, this process is only a proof of concept, but the researchers are already on their way to furthering the technique, and are currently investigating if human iMS cells can be transformed and repair tissue damage in mice.

The researchers also want to look into how the cells act at the sites of transplantation. If all goes well, human trials are expected for late 2017.

The first trials will focus on whether the iMS cells can heal bone, joint, and muscle tissue, helping to improve treatment for chronic back pain and injuries.

This research has been published in the Proceedings of the National Academy of Sciences.

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