StemCell Therapy

Cell therapies present unique challenges when complying with this paradigm for several reasons only two of which I will mention here.  Firstly, it is not possible to achieve the level of product purification as one might with other therapeutic products.  Secondly, the product characterization is at a cellular rather than molecular level.

Autologous cell therapies present another set of unique challenge in this paradigm because of the notable patient-to-patient variability where the patient is also the donor of the raw material.  This often means there is a wider tolerance of heterogeneity in the product but it still must be within what has been proven to the regulatory agency as a safe and effective range.  


In cases where an autologous cell therapy is centrally manufactured, they are most often subjected to product release testing similar to that described above.  One notable difference, particularly for fresh products, is that the products may be shipped to the clinic and even administered before the full panel of test results are obtained.  This wold be considered highly unusual (if ever acceptable) with other types of products but is tolerated because of the time-sensitivity of these products and their high safety profile.


In the case of autologous cell therapy products produced at the bedside there is often not the same kind of product release discipline.  Often the regulatory agencies deal with the product consistency and specification compliance issue by ensuring that the cell processing device used point-of-care is validated to ensure the cellular product output is always within a specified range shown to be clinically safe and effective.


The Varying Degree of Product Characterization/Specification of Autologous GTP Cell Therapy Products


However - and now I get to the point of this blog post - for cell-based products, procedures and/or devices/kits which are not mandated to be formally approved by a regulatory agency before they can be commercially marketed, there is no product specification rigor.  Compliance with the Good Tissue Practice regulations and guidance is deemed to ensure safety.  In the United States, cell-based products which are deemed to be "minimally manipulated" and intended for "homologous use" are typically allowed to go straight to market with no formal approval.  Safety and clinical data is not required but is practically necessary to support physician adoption and, where applicable, reimbursement.  


This means that for these products there is a great deal of variability in terms of how much rigor companies apply in characterizing their product and then ensuring that each batch complies with the specifications they themselves have determined to be safe and effective. Again, where such products are manufactured in a centralized facility the likelihood of some release testing is greater.  However, those companies relying on a point-of-care processing kit or device business model that has not been deemed to require formal market approval, rarely (if ever) include product release testing.


The common criticism of these companies is that they simply do not know what they are injecting into patients because of the combination of the patient-to-patient donor variability, the lack of any disciplined product characterization or dosing studies, and the absence of any product release testing.  


This criticism is not equally levied at all autologous GTP products or companies - even those relying on point-of-care processing.  Of course some companies care and do a lot to try to ensure their product is well-characterized and that each batch complies with product specifications. This may involve the use of product release tests but can also involve the combination of pre-market research into the product characterization, safety, and dosing along with validation of the device/kit output.  In this way a company can say that within a very small margin, the output will be within the product specifications the company knows is safe and efficacious.


However, in a rush to get their device/kit to market some companies appear to care very little about the cell product characterization, validation of the output of their device/kit, or tying this data to optimal dose.


More concerning are those companies that appear to provide such data but it is wrong or meaningless.  What follows appears to potentially be a case study of precisely this problem. 


The INCELL Study 


This week I came across a fascinating white paper from Incell Corporation analyzing the output of adipose tissue processing kits of MediVet-America apparently demonstrating the inaccuracy of their cell counts (a common type of cell therapy product characterization) and calling into the question the cell count claims of Intellicell Biosciences (New York, NY) and Adistem (Hong Kong).


At the heart of the critique is the claim that the cell counting (product characterization) techniques employed by these companies counts as cells things (namely acellular micelles) which are not cells.

I encourage you to read the white paper in its entirety.  They corresponding author told me to watch for one or more papers which they are preparing for submission to peer-reviewed publications shortly.  Presumably these will rely on a larger data set and perhaps test other methodologies or technologies.


For the purposes of this blog, I've pulled what I believe are the most salient excerpts below:

Intrigued by the high cell numbers  (5 to 20 million cells/gram)  reported by kit/device manufacturers such as MediVet-America (Lexington, KY), Intellicell  Biosciences (New York, NY), and Adistem, Ltd. (Hong Kong) in adipose stem cell therapy compared to other methods (e.g., 
Chung,Vidal, and Yoshimura), INCELL staff conducted a research study to  investigate the high apparent yield of stem cells.  This initial work was focused  on SVF cells from the MediVet Kit, which is marketed to isolate adiposederived canine SVF and stem cells.

The cell yields reported for the Medivet Kits are five to more than ten times higher than the yields routinely obtained by INCELL from freshly harvested human or animal adipose tissue using our adipose tissue processing methods.  These yields are also tenfold or higher than those reported in the literature by most academic researchers (Chung-canine, Vidal–equine, Yoshimura–human).  Since these  cell counts are used to support stem cell dosing recommendations and cell banking, it is important to better understand why the cell numbers are higher.

...

A comparative analytical study of three dog donors of adipose tissue was designed to evaluate the cell yields using the MediVet Kit as an example of this class of isolation system. All  kit procedures were followed as per the instructions provided.  A brief overview of the different cell counting methods used, and the resultant cell counts, observations and explanations of the results observed, are described below

....

This study shows that incorrect counting of adipose derived SVF cells and the subset of regenerative stem cells can subsequently result in inaccurate dosing, both in direct therapeutic applications and in cryostorage of cells for future use.  The DAPI-hemocytometer cell count (manual) was considered the most accurate, but there are various sources of technical difficulties that  can lead to incorrect  cell numbers. The nature of adipose tissue itself with variability in dissociation by enzymatic digestion can all contribute to the outcomes. Fat tissue has a propensity to form acellular micelles and oils upon tissue disruption. Processing methods or reagents (e.g., Solution E or lecithins) can generate micelles that may be  erroneously  counted as cells. Autofluorescence and dye trapping or uptake by the micelles can lead to very high inaccurate cell counts when automated cell counting is used. 

In this study the most inaccurate counting came from the Cellometer. When used according to kitrecommended guidelines and on-site training provided by Nexelcom for counting  cells by the MediVet procedure, the Cellometer overstated the DAPI-hemocytometer cell count by up to 20X or more. The Coulter Counter protocols also led to incorrect, high cell numbers. Although the cell counts were still a bit high, the authors recommend the NucleoCounter, or similar equipment, as more acceptable for automated counting.  The manual hemocytometer-DAPI method is the most accurate, but requires a highly experienced cell biologist or technician to make accurate counts and  is not suitable for routine clinical use. 

...

Other companies also have claims of very high cell numbers when their processes are used. Adistem, like MediVet, states they add an emulsifying agent to their kits to assist in cell release, and they also use a light activation system. Their kits were not tested in this study but it is possible that the high cell numbers reported by Adistem are also incorrect and result from the same problems highlighted in this paper for the MediVet procedure. Ultrasonic energy, which is commonly used to manufacture micellular  liposome  structures and to disrupt and lyse cells, is  another potentially problematic procedure for counting and verifying viable, regenerative cells.  Intellicell 3uses ultrasonic energy to release cells from adipose tissue, and it is possible that resultant micelles or cell fragments contribute to the higher than expected cell numbers.  This assumption could be verified with additional studies.  

In summary, the authors caution that great care must be taken when using kits and automated cell counting for stem cell dosing and cryobanking of cells intended for clinical use. Overestimated  cell numbers would be a major confounding source of variation when efficacy of stem cells injected are compared as doses based on cell number and when cryostored cells are aliquoted for use based on 

specific cell numbers as a treatment dose.  Hopefully, this study will lead to more  reproducible counting and processing methods being reported in the literature, more inter-study comparability of cell doses to clinical outcomes,  more industry diligence to support claims, and more accurate counting for dosing stem cell therapies to patients.

...

Chung D, Hayashi K, Toupadakis A, et al.  Osteogenic proliferation and differentiation of canine bone marrow and adipose tissue derived mesenchymal stromal cells and the influence of hypoxia.  Res Vet Sci, 2010; 92(1):66-75. Vidal MA, Kilroy GE, Lopez MJ, Johnson JR, Moore RM, Gimble JM. Characterization of equine adipose tissue-derived stromal cells: adipogenic and osteogenic capacity and comparison with bone marrow-derived mesenchymal stromal cells. Vet Surg, 2007; 36:613–622.  Yoshimura K, Shigeura T, Matsumoto D, et al:  Characterization of freshly isolated and cultured cells derived from the fatty and fluid portions of liposuction aspirate.  J Cell Phys, 2006; 205:64-76.

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The chairs are shifting a tad on the
governing board of the $3 billion California stem cell agency as a
French immigrant is added, a Latino leaves and a veteran patient
advocate is reappointed.

Anne-Marie Duliege Affymax Photo

State Controller John Chiang appointed
Duliege to the CIRM post, saying, 

“Dr. Duliege brings
first-hand knowledge of what is required to take a drug from research
phase through FDA approval.”

David Serrano Sewell CIRM Photo

Serrano Sewell, who has also served on
the CIRM board since its inception, is apparently resigning to accept
an appointment to the board that regulates
California physicians. Apparently – because the stem cell agency
has not confirmed that he is leaving, although this morning it placed a resolution honoring him on the agenda for next week's meeting.  That almost invariably means a board member is departing.

Jeff Sheehy CIRM Photo

Sheehy was reappointed recently by
state Senate President Pro Tem Darrell Steinberg. Sheehy is a
communications manager at UC San Francisco and a nationally known
HIV/AIDS advocate. He is co-chairman of CIRM's Science Subcommittee
and vice chairman of the grants review group. Sheehy leads the
discussion of grant applications when they come before the full board
in public session.

Source:
http://californiastemcellreport.blogspot.com/feeds/posts/default?alt=rss

A robust discussion has arisen
concerning Bob Klein and his appearance last month before the
governing board of the $3 billion California stem cell agency, a body
that he once chaired and an enterprise that he once oversaw.

Source:
http://californiastemcellreport.blogspot.com/feeds/posts/default?alt=rss

Four researchers are appealing
rejection of their proposals to win millions of dollars from the
California stem cell agency just as the agency is moving to curb such
reconsideration efforts by scientists.

Source:
http://californiastemcellreport.blogspot.com/feeds/posts/default?alt=rss

The $3 billion California stem cell
agency on Tuesday released details of proposed, major changes in how
scientists are allowed to appeal decisions when their
applications for millions of dollars are rejected by grant reviewers.

"I don't think we can run a board
this way. If we do, it would be chaos." 

“So a project that was really going
to go into patients was essentially triaged.”

Source:
http://californiastemcellreport.blogspot.com/feeds/posts/default?alt=rss

Researchers from the University of
Southern California are making a pitch to overturn rejection of their
$20 million grant application by reviewers in one of the signature
commercialization rounds of the California stem cell agency.

“We are submitting the petition at
this time as we are new to the CIRM ICOC(governing board) process and after listening
to the July 26 ICOC meeting deliberations now understand that the
petition process allows the ICOC to further consider our proposal.
We noted that the proposal scored one point above ours and another
two points below ours, each utilized the extraordinary petition
strategy to gain ICOC review which resulted in funding approval in
the former, and reconsideration in the latter instance.”

“I'm not really quire sure that all
of the applicants clearly understood that they could come back to us
to address the criticisms(of reviewers).”

Concerns about whether all applicants fully understand the appeal process have surfaced on a number of occasions over the last several years. The CIRM board, however, is generally reluctant to overturn negative recommendations by reviewers. It also almost never reverses positive recommendations.

Source:
http://californiastemcellreport.blogspot.com/feeds/posts/default?alt=rss

Directors of the California stem cell
agency next week are expected to make unspecified changes in how
scientists can appeal denials of their applications for millions of
dollars in research grants.

Source:
http://californiastemcellreport.blogspot.com/feeds/posts/default?alt=rss

YAHOO:

Talent manager Annabelle Rama will fly to Germany in September to undergo therapy - stem cell therapy, that is. This has been a promise made by her son Richard Gutierrez who's footing the bill. "Early this year pa lang ay napagplanuhan na 'yung pagpapa-stem cell ng nanay ko at prinomise ko sa kanya na pag-iipunan ko, prinomise ko sa kanya na ako ang magti-treat sa kanya," Richard said on the first episode of "H.O.T. TV," Aug. 5.

He noted, "'Yung mom ko hindi mahilig 'yan na pumunta sa mga doctor, hindi mahilig magpa-check-up."

Looking forward

This early, Annabelle is already excited about her trip and the upcoming treatment.

"Kaya ako excited pumunta kasi unang-una mataas ang aking sugar, mataas ang aking cholesterol, tapos me problema pa ako sa high blood, blood pressure ko. Siguro nga kailangan kong pumunta ng Germany," she said, noting that the condition of her friends, talent manager Lolit Solis and actress Lorna Tolentino, have improved tremendously after going through stem cell therapy.

"Nakita ko ang mukha ni Lolis pumuputi ang mukha niya, eh at saka mukha siyang fresh na fresh. Lalo na si LT, nakita ko rin siya. Mukhang gumanda naman siya. Basta lahat ng kaibigan kong galing doon, nakakausap ko, sabi nila ay talagang gumaling daw sila. 'Yung kanilang napi-feel na mabigat sa katawan dahil sa sakit nila ay nawawala lahat," she said.

Exorbitant fees?

Annabelle had already inquired about the fees of stem cell procedure in the country and she feels it's exorbitant.

"Kasi sa Piipinas may pinagtatanungan na ako, umabot ng mga four million pesos 'yung naitanong ko kaya parang na-discourage akong magpagamot kasi nga ganoon kamahal."

More here:
Annabelle Rama to undergo stem cell treatment to improve health

YAHOO:

Talent manager Annabelle Rama will fly to Germany in September to undergo therapy - stem cell therapy, that is. This has been a promise made by her son Richard Gutierrez who's footing the bill. "Early this year pa lang ay napagplanuhan na 'yung pagpapa-stem cell ng nanay ko at prinomise ko sa kanya na pag-iipunan ko, prinomise ko sa kanya na ako ang magti-treat sa kanya," Richard said on the first episode of "H.O.T. TV," Aug. 5.

He noted, "'Yung mom ko hindi mahilig 'yan na pumunta sa mga doctor, hindi mahilig magpa-check-up."

Looking forward

This early, Annabelle is already excited about her trip and the upcoming treatment.

"Kaya ako excited pumunta kasi unang-una mataas ang aking sugar, mataas ang aking cholesterol, tapos me problema pa ako sa high blood, blood pressure ko. Siguro nga kailangan kong pumunta ng Germany," she said, noting that the condition of her friends, talent manager Lolit Solis and actress Lorna Tolentino, have improved tremendously after going through stem cell therapy.

"Nakita ko ang mukha ni Lolis pumuputi ang mukha niya, eh at saka mukha siyang fresh na fresh. Lalo na si LT, nakita ko rin siya. Mukhang gumanda naman siya. Basta lahat ng kaibigan kong galing doon, nakakausap ko, sabi nila ay talagang gumaling daw sila. 'Yung kanilang napi-feel na mabigat sa katawan dahil sa sakit nila ay nawawala lahat," she said.

Exorbitant fees?

Annabelle had already inquired about the fees of stem cell procedure in the country and she feels it's exorbitant.

"Kasi sa Piipinas may pinagtatanungan na ako, umabot ng mga four million pesos 'yung naitanong ko kaya parang na-discourage akong magpagamot kasi nga ganoon kamahal."

Read more from the original source:
Annabelle Rama to undergo stem cell treatment to improve health

Research and MarketsPosted on:31 Aug 12

Research and Markets (http://www.researchandmarkets.com/research/9fkkzb/cell_therapy_tec) has announced the addition of Jain PharmaBiotech's new report "Cell Therapy - Technologies, Markets and Companies" to their offering.

This report describes and evaluates cell therapy technologies and methods, which have already started to play an important role in the practice of medicine. Hematopoietic stem cell transplantation is replacing the old fashioned bone marrow transplants. Role of cells in drug discovery is also described. Cell therapy is bound to become a part of medical practice.

Stem cells are discussed in detail in one chapter. Some light is thrown on the current controversy of embryonic sources of stem cells and comparison with adult sources. Other sources of stem cells such as the placenta, cord blood and fat removed by liposuction are also discussed. Stem cells can also be genetically modified prior to transplantation.

Cell therapy technologies overlap with those of gene therapy, cancer vaccines, drug delivery, tissue engineering and regenerative medicine. Pharmaceutical applications of stem cells including those in drug discovery are also described. Various types of cells used, methods of preparation and culture, encapsulation and genetic engineering of cells are discussed. Sources of cells, both human and animal (xenotransplantation) are discussed. Methods of delivery of cell therapy range from injections to surgical implantation using special devices.

Cell therapy has applications in a large number of disorders. The most important are diseases of the nervous system and cancer which are the topics for separate chapters. Other applications include cardiac disorders (myocardial infarction and heart failure), diabetes mellitus, diseases of bones and joints, genetic disorders, and wounds of the skin and soft tissues.

Regulatory and ethical issues involving cell therapy are important and are discussed. Current political debate on the use of stem cells from embryonic sources (hESCs) is also presented. Safety is an essential consideration of any new therapy and regulations for cell therapy are those for biological preparations.

The cell-based markets was analyzed for 2011, and projected to 2021. The markets are analyzed according to therapeutic categories, technologies and geographical areas. The largest expansion will be in diseases of the central nervous system, cancer and cardiovascular disorders. Skin and soft tissue repair as well as diabetes mellitus will be other major markets.

The number of companies involved in cell therapy has increased remarkably during the past few years. More than 500 companies have been identified to be involved in cell therapy and 284 of these are profiled in part II of the report along with tabulation of 274 alliances. Of these companies, 154 are involved in stem cells. Profiles of 70 academic institutions in the US involved in cell therapy are also included in part II along with their commercial collaborations. The text is supplemented with 55 Tables and 11 Figures. The bibliography contains 1,050 selected references, which are cited in the text.

Key Topics Covered:

Read the original:
Press Release

DUBLIN--(BUSINESS WIRE)--

Research and Markets (http://www.researchandmarkets.com/research/9fkkzb/cell_therapy_tec) has announced the addition of Jain PharmaBiotech's new report "Cell Therapy - Technologies, Markets and Companies" to their offering.

This report describes and evaluates cell therapy technologies and methods, which have already started to play an important role in the practice of medicine. Hematopoietic stem cell transplantation is replacing the old fashioned bone marrow transplants. Role of cells in drug discovery is also described. Cell therapy is bound to become a part of medical practice.

Stem cells are discussed in detail in one chapter. Some light is thrown on the current controversy of embryonic sources of stem cells and comparison with adult sources. Other sources of stem cells such as the placenta, cord blood and fat removed by liposuction are also discussed. Stem cells can also be genetically modified prior to transplantation.

Cell therapy technologies overlap with those of gene therapy, cancer vaccines, drug delivery, tissue engineering and regenerative medicine. Pharmaceutical applications of stem cells including those in drug discovery are also described. Various types of cells used, methods of preparation and culture, encapsulation and genetic engineering of cells are discussed. Sources of cells, both human and animal (xenotransplantation) are discussed. Methods of delivery of cell therapy range from injections to surgical implantation using special devices.

Cell therapy has applications in a large number of disorders. The most important are diseases of the nervous system and cancer which are the topics for separate chapters. Other applications include cardiac disorders (myocardial infarction and heart failure), diabetes mellitus, diseases of bones and joints, genetic disorders, and wounds of the skin and soft tissues.

Regulatory and ethical issues involving cell therapy are important and are discussed. Current political debate on the use of stem cells from embryonic sources (hESCs) is also presented. Safety is an essential consideration of any new therapy and regulations for cell therapy are those for biological preparations.

The cell-based markets was analyzed for 2011, and projected to 2021. The markets are analyzed according to therapeutic categories, technologies and geographical areas. The largest expansion will be in diseases of the central nervous system, cancer and cardiovascular disorders. Skin and soft tissue repair as well as diabetes mellitus will be other major markets.

The number of companies involved in cell therapy has increased remarkably during the past few years. More than 500 companies have been identified to be involved in cell therapy and 284 of these are profiled in part II of the report along with tabulation of 274 alliances. Of these companies, 154 are involved in stem cells. Profiles of 70 academic institutions in the US involved in cell therapy are also included in part II along with their commercial collaborations. The text is supplemented with 55 Tables and 11 Figures. The bibliography contains 1,050 selected references, which are cited in the text.

Key Topics Covered:

Read more:
Research and Markets: Cell Therapy - Technologies, Markets and Companies - Updated 2012 Report

Newswise UCLA researchers have discovered a type of cell that is the missing link between bone marrow stem cells and all the cells of the human immune system, a finding that will lead to a greater understanding of how a healthy immune system is produced and how disease can lead to poor immune function.

The studies were done using human bone marrow, which contains all the stem cells that produce blood during postnatal life.

We felt it was especially important to do these studies using human bone marrow as most research into the development of the immune system has used mouse bone marrow, said study senior author Dr. Gay Crooks, co-director of the Eli and Edythe Broad Center of Regenerative Medicine and a co-director of the Cancer and Stem Cell Biology program at UCLAs Jonsson Comprehensive Cancer Center. The few studies with human tissue have mostly used umbilical cord blood, which does not reflect the immune system of postnatal life.

The research team was intrigued to find this particular bone marrow cell because it opens up a lot of new possibilities in terms of understanding how human immunity is produced from stem cells throughout life, said Crooks, a professor of pathology and pediatrics.

Understanding the process of normal blood formation in human adults is a crucial step in shedding light on what goes wrong during the process that results in leukemias, or cancers of the blood.

The study appears Sept. 2 in the early online edition of Nature Immunology.

Before this study, researchers had a fairly good idea of how to find and study the blood stem cells of the bone marrow. The stem cells live forever, reproduce themselves and give rise to all the cells of the blood. In the process, the stem cells divide and produce intermediate stages of development called progenitors, which make various blood lineages like red blood cells or platelets. Crooks was most interested in the creation of the progenitors that form the entire immune system, which consists of many different cells called lymphocytes, each with a specialized function to fight infection.

Like the stem cells, the progenitor cells are also very rare, so before we can study them we needed to find the needle in the haystack. said Lisa Kohn, a member of the UCLA Medical Scientist Training Program and first author in the paper.

Previous work had found a fairly mature type of lymphocyte progenitor with a limited ability to differentiate, but the new work describes a more primitive type of progenitor primed to produce the entire immune system, Kohn said

Once the lymphoid primed progenitor had been identified, Crooks and her team studied how gene expression changed during the earliest stages of its production from stem cells.

Go here to read the rest:
UCLA Researchers Discover "Missing Link" Between Stem Cells and the Immune System

With its world-renowned biomedical engineering program, School of Medicine and School of Veterinary Medicine, the University of California, Davis, brings a constellation of expertise to bear on the field of bone regeneration and repair.

Here are some of the UC Davis scientists engaged in bone-repair research:

Professor A. Hari Reddi holds the Lawrence Ellison Chair in Orthopedics at UC Davis. He has studied bone regeneration for more than 40 years and joined the faculty at UC Davis in 1997. His laboratory at the National Institutes of Health was the first to purify bone morphogenetic protein in the 1980s. His laboratory is studying the role of bone morphogenetic proteins in tissue engineering and regeneration of articular cartilage, with an eye toward helping patients with osteoarthritis. Although initially thought of in relation to bone, these proteins are now shown to be involved in brain, cartilage, kidney, lung, tooth and nerve differentiation as well as in heat regulation and iron metabolism, Reddi says. He has proposed changing the name to "body morphogenetic proteins" in view of their versatile role in the human body.

"BMPs are one of the most exciting chapters in modern developmental biology," he says.

More information: http://www.ucdmc.ucdavis.edu/ctrr/research/reddi.html

Understanding the healing and regeneration of cartilage is the aim of the Musculoskeletal Bioengineering Laboratory led by Professor Kyriacos Athanasiou, chair of the Department of Biomedical Engineering at UC Davis. Cartilage forms the hard covering at the ends of bones. Tissues such as the knee meniscus have to deal with demanding loads but show little or no ability to regenerate by themselves.

Athanasiou's lab aims to understand the healing processes of cartilage, and to augment those processes through tissue engineering. Their approach uses both biomechanical techniques and bioactive agents and signals. They are also interested in stem cell technologies to repair cartilage and connective tissue.

The team has partnered with surgeons at the UC Davis Veterinary Medical Teaching Hospital to regrow jawbones for dogs that have lost part of their jaw due to cancer or injury. The technique uses a sponge-like scaffolding impregnated with bone morphogenetic protein, which is inserted into the space where the bone was removed. The growth-promoting protein stimulates the dogs remaining jawbone to grow new bone cells, eventually filling the entire defect and integrating with the native bone.

More information: http://www.bme.ucdavis.edu/athanasioulab/

Kent Leach, associate professor of biomedical engineering, is working with matrix materials that encourage the growth of new bone from stem cells. With funding from The Hartwell Foundation, he is working on treatments that could be used in babies with craniosynostosis, a condition where the bones of the skull fuse too early. In a project funded by the U.S. Department of Defense, Leach is studying a gel-like matrix that can be seeded with adult stem cells from fat and used to heal bone fractures more rapidly.

See the original post:
Bone repair research at UC Davis

The molecular circuitry controlling asymmetric cell division in roots resembles a flip-flop switch.

(Phys.org)For organisms to grow and develop, they must produce tissues with distinct functions, each one made up of similar cells. These different tissues are derived from stem cells. How stem cells divide to create new cell types is known as asymmetric cell division, and is obviously crucial to the overall development of the organism. In plants, whose cells cannot migrate, the location where a stem cell undergoes asymmetric cell division must also be crucial to ensuring tissues develop in the correct place.

In research published in the journal Cell, a collaboration between theoretical biologists and experimentalists, headed by Stan Mare of the John Innes Centre, and Ben Scheres, of the University of Utrecht, the Netherlands, uncovered a molecular switch that integrates signals to ensure these asymmetric cell divisions happen in the right place and at the right time, to produce layers of specialised tissue in the root.

"Through an experimental-modelling cycle, we have unravelled how stem cells in the Arabidopsis root regulate asymmetric cell divisions that give rise to two new cell identities at the correct position," said Dr Stan Mare of the John Innes Centre, which is strategically funded by the Biotechnology and Biological Sciences Research Council. "We dissected the underlying molecular circuit which operates in each cell, and found that it presented a highly robust bistable behaviour, due to two positive feedback loops involving the proteins SHR, SCR and the cell-cycle related players RBR and CYCLD6;1. In other words, we showed that the circuit behaves like a switch."

Bistable systems, which can only exist in one of two states, are found in nature where tight control is needed. Positive feedback loops are common features of them as they help make the rapid switch from one state to another.

Having identified this switch, the next step was to work out how the plant turns it on and off, so that only the correct stem cells perform asymmetric division, and in the right location for the overall development of the plant.

To do this, Dr Stan Mare together with Dr Vernica Grieneisen constructed a mathematical model, an in silico version of the root and the molecular circuitry behind the switch.

The physical location of an asymmetric cell division relies on the interaction of the plant hormone auxin and the protein SHR. Previous work by Dr Grieneisen had shown how auxin accumulates in the root tip through a reflux-loop mechanism established by polarly localized auxin efflux carriers in cells, and that the concentration of auxin declines the further from the root tip, forming a gradient with its highest peak at the stem cells.SHR protein sets up a similar gradient, but perpendicular to the auxin gradient, radiating out.

"We found that the cells that undergo these special cell divisions are located right at the crossroads of these two gradients," said Dr Grieneisen.

The cell divisions also trigger protein degradation, which turns the switch off again. This is needed to prevent uncontrolled development.

Original post:
'Flip-flop' switch discovered behind key cellular process

ScienceDaily (Aug. 30, 2012) The skin, the blood, and the lining of the gut -- adult stem cells replenish them daily. But stem cells really show off their healing powers in planarians, humble flatworms fabled for their ability to rebuild any missing body part. Just how adult stem cells build the right tissues at the right times and places has remained largely unanswered.

Now, in a study published in an upcoming issue of Development, researchers at the Stowers Institute for Medical Research describe a novel system that allowed them to track stem cells in the flatworm Schmidtea mediterranea. The team found that the worms' stem cells, known as neoblasts, march out, multiply, and start rebuilding tissues lost to amputation.

"We were able to demonstrate that fully potent stem cells can mobilize when tissues undergo structural damage," says Howard Hughes Medical Institute and Stowers Investigator Alejandro Snchez Alvarado, Ph.D., who led the study. "And these processes are probably happening to both you and me as we speak, but are very difficult to visualize in organisms like us."

Stem cells hold the potential to provide an unlimited source of specialized cells for regenerative therapy of a wide variety of diseases but delivering human stem cell therapies to the right location in the body remains a major challenge. The ability to follow individual neoblasts opens the door to uncovering the molecular cues that help planarian stem cells navigate to the site of injury and ultimately may allow scientists to provide therapeutic stem cells with guideposts to their correct destination.

"Human counterparts exist for most of the genes that we have found to regulate the activities of planarian stem cells," says Snchez Alvarado. "But human beings have these confounding levels of complexity. Planarians are much simpler making them ideal model systems to study regeneration."

Scientists had first hypothesized in the late 1800s that planarian stem cells, which normally gather near the worms' midlines, can travel toward wounds. The past century produced evidence both for and against the idea. Snchez Alvarado, armed with modern tools, decided to revisit the question.

For the new study, first author Otto C. Guedelhoefer, IV, Ph.D., a former graduate student in Snchez Alvarado's lab, exposed S. mediterranea to radiation, which killed the worms' neoblasts while leaving other types of cells unharmed. The irradiated worms would wither and die within weeks unless Guedelhoefer transplanted some stem cells from another worm. The graft's stem cells sensed the presence of a wound -- the transplant site -- migrated out of the graft, reproduced and rescued their host. Unlike adult stem cells in humans and other mammals, planarian stem cells remain pluripotent in fully mature animals and remain so even as they migrate.

But when Guedelhoefer irradiated only a part of the worm's body, the surviving stem cells could not sense the injury and did not mobilize to fix the damage, which showed that the stem cells normally stay in place. Only when a fair amount of irradiated tissue died did the stem cells migrate to the injured site and start to rebuild. Next, Guedelhoefer irradiated a worm's body part and cut it with a blade. The surviving stem cells arrived at the scene within days.

To perform the experiments, Guedelhoefer adapted worm surgery and x-ray methods created sixty to ninety years ago. "Going back to the old literature was essential and saved me tons of time," says Guedelhoefer, currently a postdoctoral fellow at the University of California, Santa Barbara. He was able to reproduce and quantify results obtained in 1949 by F. Dubois, a French scientist, who first developed the techniques for partially irradiating planarians with x-rays.

But Guedelhoefer went further. He pinpointed the locations of stem cells and studied how far they dispersed using RNA whole-mount in situ hybridization (WISH), specifically adapted to planarians in Snchez Alvarado's lab. Using WISH, he observed both original stem cells and their progeny by tagging specific pieces of mRNA . The technique allowed him to determine that pluripotent stem cells can travel and produce different types of progeny at the same time.

Originally posted here:
Moving toward regeneration

Stem Cells Inc, (STEM), developer of stem cell-based treatments for spinal injury, is up for the second day in a row Friday in pre-market trading, after it closed Thursday at $1.96, a 19% gain on the day. The gains came after the company announced that it will be presenting data from its Phase I/II clinical trial on Monday, Sept. 3 at the International Spinal Cord Society and will hold a conference call the following day. Trading volume Thursday was three times its 3-month average. The presentation will include interim data from the study`s first cohort, which has three partially paralyzed patients being treated with STEM`s proprietary HuCNS-SC cells. Researchers are looking for efficacy - measured by improvement in motor function, sensation, and bladder control - and safety in the first of three planned cohorts, each with more mild paralysis than the previous. Share price is likely to remain strong on Friday and into the meeting, as most analysts expect some positive results from the trial. If Monday`s data looks good for STEM, shares may climb higher on momentum, however, negative results will have disastrous effects on the stock. STEM is up 140% in 2012.

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PropThink: STEM Gains on Anticipation of Interim Trial Data to be Presented Monday

Stem cell-powered implant set to revolutionise orthopaedic surgery

Scientists at the University of Glasgow are working to harness the regenerative power of stem cells to improve orthopaedic implant surgery. They are collaborating with surgeons at Glasgows Southern General Hospital to develop a new type of orthopaedic implant which could be considerably stronger and more long-lived than the current generation of products.

Currently, implants are commonly made from materials such as polyethylene, stainless steel, titanium or ceramic and have a limited lifespan due to loosening, requiring replacement after 15 or 20 years of use. In hip replacement surgery, the head of the thigh bone is removed and replaced with an implant which is held in place by a rod fixed inside the marrow along the length of the bone.

Marrow is a rich source of mesenchymal stem cells, which have the potential to divide, or differentiate, into other types of cells such as skin, muscle or bone which can improve the process of healing. However, stem cells can also differentiate into cells which have no use in therapy. Artificially controlling the final outcome to ensure the desired type of cells are created is very difficult, even under laboratory conditions.

When traditional implants are fixed into bone marrow, the marrows stem cells do not receive messages from the body to differentiate into bone cells, which would help create a stronger bond between the implant and the bone. Instead, they usually differentiate into a buildup of soft tissue which, combined with the natural loss of bone density which occurs as people age, can weaken the bond between the implant and the body.

The team from the University of Glasgows Colleges of Science and Engineering and Medical, Veterinary and Life Sciences have found a reliable method to encourage bone cell growth around a new type of implant. The implant will be made of an advanced implantable polymer known as PEEK-OPTIMA, from Invibio Biomaterial Solutions, which is already commonly used in spinal and other orthopaedic procedures.

Dr Matthew Dalby, of the Universitys Institute of Molecular, Cell and Systems Biology, explained: Last year, we developed a plastic surface which allowed a level of control over stem cell differentiation which was previously impossible. The surface, created at the Universitys James Watt Nanofabrication Centre, is covered in tiny pits 120 nanometres across. When stem cells are placed onto the surface, they grow and spread across the pits in a way which ensures they differentiate into therapeutically useful cells.

By covering the PEEK implant in this surface, we can ensure that the mesenchymal stem cells differentiate into the bone cells. This will help the implant site repair itself much more effectively than has ever been possible before and could well mean that implants will last for the rest of patients life.

Dr Dalby added: People are living longer and longer lives nowadays; long enough, in fact, that were outliving the usefulness of some of our body parts. Our new implant could be the solution to the expensive and painful follow-up surgeries which conventional implants require.

Dr Nikolaj Gadegaard, Senior Lecturer in Biomedical Engineering at the University, explained: One of the main selling points of PEEK is that it is very strong, has excellent stability and is very resistant to wear. However, the inertness of the material is not always suitable for implants that require some interaction with the surrounding tissue. Our nanopatterned surface may allow Invibios PEEK polymer to interact with stem cells and enable an effective integration between the implant and the body for the first time.

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Stem cells power implants

In past years, these nine little letters, stem cells, have caused much controversy and misunderstanding.

Stem cells are primitive, undifferentiated cells that are able to divide and become specialized cells of the body such as liver cells, muscle cells, blood cells and other cells with specific functions.

Because they have not yet committed to a developmental path that will form a specific tissue or organ, they are considered master cells with great potential. You may have wondered about what they are used for, and if they hold promise for helping you or a family member with serious disease or injury.

Stem cells are interesting and useful to doctors and scientists for several reasons:

Further work includes potential treatment for Type 1 diabetes, arthritis, stroke, Parkinsons disease, heart disease and Alzheimers disease.

There are also cosmetic applications, using the patients own cells for facial and body enhancement, such as the stem cell facelift, and topical skin applications.

The different types of stem cells include:

These come from embryos that are four to five days old, usually left over from fertility treatments and voluntarily donated.

These were thought to have the most potential for scientific use because they had minimal exposure to potential environmental toxins and great potential for use in tissue and organ regeneration. They are able to self-renew and are pluri-potent, meaning they become any type of cell in the future.

Embryonic cells are also the source of great controversy and debate, since many of us believe that life begins at conception and that manipulation of embryonic stem cells is unethical.

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Positively Beautiful: Ever wondered about stem cells?

Public release date: 28-Aug-2012 [ | E-mail | Share ]

Contact: Leslie Orr Leslie_Orr@urmc.rochester.edu University of Rochester Medical Center

University of Rochester Medical Center scientists believe they are the first to identify genes that underlie the growth of primitive leukemia stem cells, and then to use the new genetic signature to identify currently available drugs that selectively target the rogue cells.

Although it is too early to attach significance to the drug candidates, two possible matches popped up: A drug in development for breast cancer (not approved by the Food and Drug Administration), and another experimental agent that, coincidentally, had been identified earlier by a URMC laboratory as an agent that targets leukemia cells.

The research not only provides a better understanding of the basic biology of leukemia it uncovered genes not previously known to be associated with the disease -- but demonstrates a powerful strategy for drug discovery, said senior investigator Craig T. Jordan, Ph.D., the Philip and Marilyn Wehrheim professor of Medicine at URMC and the James P. Wilmot Cancer Center.

First author John Ashton, PhD, led the study, which was published this month in the journal Cell Stem Cell.

"Our work is both basic and translational, and is an example of a terrific collaboration," Jordan said. "We were able to use the latest technology to expand very strong basic laboratory concepts and conduct an intriguing analysis that may yield new insights for treatments of leukemia."

Jordan studies leukemia stem cells, which, unlike normal cells, renew uncontrollably and are believed to be the first cells at the root of malignancy. He collaborated with Hartmut (Hucky) Land, Ph.D. and Helene McMurray, Ph.D., investigators in the Biomedical Genetics Dept at URMC, who study the principle that cancer evolves from a unique, interactive network of genes that are governed by a distinct set of rules.

In 2008 Land's laboratory published a paper in Nature reporting on a pool of approximately 100 genes that cooperate to promote colon cancer. The Land laboratory coined the term CRG for "cooperation response genes," to emphasize the special synergy controlling this pool of genes. Land is the Robert and Dorothy Markin Professor and Chair of the Department of Biomedical Genetics at URMC, and co-director of the Wilmot Cancer Center.

The identification of CRGs broadened the view of cancer, Jordan said. Historically, scientists would study the intricacies of one or two individual pathways in a vast network of alterations. With the advent of CRGs, however, researchers now have a better picture of the sub-populations of genes that dole out instructions to primitive cancer cells, like controls on a circuit board. Depending on whether CRGs are turned off or on, patterns change and cancer either progresses or stops, Land's research showed.

Original post:
URMC researchers connect new genetic signature to leukemia

A cure for spinal cord injury? Diabetes? Macular degeneration? Hope or just hype? There are now some clinical trials using embryonic stem cells to treat serious diseases for which no other good therapy is currently available. But this is just the beginning of a major medical megatrend that will blossom forth in the coming years. Embryonic stem cells are present after a fertilized egg divides for two or three days. They have the seemingly miraculous ability to turn into any of the tissue types in the bodywhether brain neurons, beating heart cells, bone, or pancreatic islet cells. It is important to understand just where these cells come from. Those used in science are the byproduct of in vitro fertilization (IVF), cells taken from the often left over embryos that are otherwise discarded. In 1998, scientists under the leadership of Dr James Thomson at the University of Wisconsin, learned how to take some of the cells from these about to be discarded embryos and put them into a cell culture basically a fluid in which the cells can grow to produce more cells. These cells in turn can then be directed to grow into heart or lung or pancreas or other types of cells by the addition of various additives to the fluid in which they are growing. So it is from these discards that embryonic stem cells are available to us. Just to be clear. The blastocyst or embryo with its 32 or so cells is not grown in the culture dish. Rather, individual cells are removed and allowed to divide and grow. These are the so called embryonic stem cells. But no embryo is growing, just individual cells. It is true that much can be done with adult stem cells as discussed last time but science so far suggests that embryonic stem cells hold promise for much more benefit. It will probably be embryonic stem cells (or perhaps induced pluipotent stem cells see the first in this series) that pave the way for replacing the islet cells of the pancreas with new insulin producing cells to cure diabetes or replace the damaged cells in the brain that are key to Parkinsons disease. Some strongly feel that it is wrong to use cells from embryos. It is important to remember that these are fertilized eggs that were prepared for couples that could not conceive and so had eggs and sperm placed into a dish with special fluids. Experience has shown that success is better if the doctor implants a few embryos into the womans uterus rather than just one. But the doctor may have more than enough embryos and the extras will be discarded if the woman becomes pregnant. I look at it this way. Since the embryos will be destroyed anyway, why not use them for creating stem cells that perhaps many people with diverse diseases might benefit from. It is not dissimilar to transplanting the organs of a person who has died in a car accident rather than burying them in the grave. And the embryo, made up of just a few cells, is disrupted so each cell grows independently. Now the cells can be stimulated to become heart cells, liver cells or whatever and might be useful in treating a disease. It will take some years but there will certainly be major advances down the road in how we can repair, restore or replace damaged tissues or organs. The pace at which we benefit from stem cell therapy will be influenced by factors including cultural attitudes which in turn lead to legislative decisions and legal challanges. The issues revolving around federal funding via the NIH for research on embryonic stem cells reached the federal courts two summers ago and were further addressed by an appellate court in April of 2011. Cohen and Adashi, writing in the New England Journal of Medicine in May, 2011, gave a clear account of the debate in the courts. They concluded with It is difficult to overestimate the vast potential of stem-cell research. We believe we cannot afford to allow ongoing legal ambiguities to compromise this line of scientific pursuit. Quite the contrary, now is the time to pick up the pace with an eye toward realizing the hoped-for translational benefits. With statutory relief deemed unlikely to be provided before the 2012 elections, it appears all but inevitable that the matter of funding of human ESC research will have to be settled in a court of law. Of course that never happened and stem cell research is not high on the publics set of concerns for this years elections but the makeup of the coming Congress after the election could be relevant down the road. Here is an example of how stem cells could be used: islet cells on demand One day, and I believe it will occur within five to ten years, stem cells will be able to be mass grown into islet cells. They will be ready when the patient needs them. Just give them by vein and they will home into where they need to go. And if they are created from the process called nuclear transfer or adult cells reprogrammed from the patient by genes (iPSC) or proteins (piPSC) that I described previously, they probably will not be rejected because they will be developed to not provoke the immune system. But still, whatever process destroyed their own islet cells years before will probably still be functional. So these new cells may be destroyed over time as well, unless some new technology or drugs are developed to prevent this cell destruction by the body. But in the meantime, just come back for a new infusion whenever needed. Sort of like going to the gas station to refill the tank! Islet cells injected into the vein seem to know to go to the liver and live there and do their work. Bone marrow stem cells when injected by vein go to the bone marrow, take up residence and repopulate the marrow of the patient with leukemia who just got very aggressive treatments to eliminate all of his own marrow cells (and hopefully all of the leukemia cells as well.) But would all stem cells know where to go? Or what to do? Would they go to the heart after a heart attack or do they need to be infused directly into the coronary arteries or injected into the heart muscle itself? And stem cells or stem cells prompted to develop into brain cells will they need to be injected directly into those areas of the brain damaged by Parkinsons or Alzheimers diseases? These are but a few of the issues to be resolved with careful research. Here are just a few studies in progress, some in animals, some in humans and many in laboratory settings: iPS cells have been created for multiple different diseases by taking cells from affected patients such as diabetes type I, Lou Gehrigs disease (amyotrophic lateral sclerosis), Gauchers disease and muscular dystrophy. It is hoped that these cells will help explain the disease processes and their origination. In addition, they might prove useful in growing large numbers of mature cells that could in turn be used for drug screening and drug toxicity evaluations. And in this regard, iPSCs and piPSCs matured into cardiac cells are already being used by pharmaceutical companies to test new drugs for side effects. We all know that if we have a tooth pulled, thats it a tooth wont grow back. But an intriguing study has taken the cells of the progenitors of the molars from mouse embryos and grown them in culture for a few days. Meanwhile, a molar or two from multiple adult mice were extracted. Then the stem cells were implanted into that space and within two months the mice had new teeth with normal structure and strength, demonstrating that stem cells in the proper setting can lead to the re-growth of an organ or tissue. Think about the potential in humans to get a real new tooth rather than a prosthetic tooth or a bridge when a diseased or damaged tooth must be extracted. One of the most exciting studies to get underway was a phase 1 trial of stem cells in patients with spinal cord damage. The Geron Company began this FDA-approved trial in late 2010. They took human embryonic stem cells and from them derived oligodendrocyte progenitor cells; in other words, nerve cells. These were injected next to the spinal cord at the level of very recent injury. In extensive animal experiments, these cells were found able to cause the damaged spinal cord cells to remylinate (basically reapply an insulator as with the covering of an electric wire) and to create some type of nerve growth stimulation with remarkable restoration of some or all function. The rats began to move much more normally within just a week or so of the injection. Then came the human trial. It was Phase 1 meaning that it was all about studying if the injected cells would cause any toxicity. It is a good guess that they would not but because they were be used initially in low dosage (relative to what was used in the rats to obtain responses) so it is unlikely any functional improvement would occur. That would be the test in later trials (Phase 2 and 3) with higher cell numbers provided this Phase 1 study proceeded successfully. As it turned out, Geron Corporation ended the study after enrolling just four patients citing lack of adequate funding to continue. This left Advanced Cell Technology, Inc. as the only other American company conducting a study of embryonic stem cells for macular degeneration and for macular dystrophy in the eyes. They use embryonic stem cells to produce retinal epithelial pigment cells to be injected behind the retina in affected patients. Results will be forthcoming. Another very early Phase I study, this one using adult stem cells, is just beginning in Israel for amyotrophic lateral sclerosis (ALS). The patients own bone marrow stem cells will be treated in the laboratory with a proprietary process by BrainStorm Cell Therapeutics and then placed back into patients. So far 12 of 24 patients have been treated with no apparent adverse effects. The final results will be of real interest. As I said at the beginning, there is still much to be learned before stem cells will become routinely utilized for patient care but progress is real and the opportunities are exciting for a major transformation of medical care in the coming years. Here, as with genomics, we see the value and the importance of innovation. Scientists with good ideas taking the steps needed to bring new and until recently almost undreamed of possibilities to transform healthcare clearly a medical megatrend in the making.

Stephen C Schimpff, MD is an internist, professor of medicine and public policy, former CEO of the University of Maryland Medical Center and is chair of the advisory committee for Sanovas, Inc. and senior advisor to Sage Growth Partners. He is the author of The Future of Medicine Megatrends in Healthcare and The Future of Health Care Delivery- Why It Must Change and How It Will Affect You from which this post is partially adapted.

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Medical Megatrends Stem Cells — Part III