StemCell Therapy

Table of Contents Module 1 Conceptually, stem cell research can be viewed as a branch of modern biology that attempts to create stem cells from differentiated cells or to transform embryonic or adult stem cells into specialized, differentiated cells that can be used to replace damaged cells or organs. Research conducted from 1998 to 2015 on human stem cells has demonstrated that the transformation of stem cells into healthy specialized cell types is emerging as a fundamental biological area of study that could lead to revolutionary therapies and clinical applications. Many scientists are convinced that stem cell research also will lead to a better understanding of fundamental aspects of biology in the areas of cellular differentiation, organ regeneration, regenerative medicine, and epigenetics as well as the science of cancer. In this light, stem cell research simultaneously represents a domain of both critical basic research and promising clinical application. In sum, stem cell research is rapidly advancing science in profound ways, and has great potential to positively affect our health as well as our quality of life. To more fully understand the complexities that underlie stem cell biology, it is critical to appreciate the definition of terms, understanding of the embryology, and the process of generating stem cells. Soon after fertilization, the haploid egg and sperm nuclei merge to form a single nucleus with the diploid number of chromosomes. The one-cell zygote divides as it moves along in the fallopian tube, where it continues to divide. Up until the 8-cell stage, each cell is totipotent.

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Totipotent means that each cell can give rise to all the 220 cell types in the embryo plus the extra-embryonic tissues necessary to form the placenta and yolk sac that together allow for the development of the fetus. The ability to form the placenta is a defining feature of totipotent cells.

Soon after fertilization, the haploid egg and sperm nuclei merge to form a single nucleus with the diploid number of chromosomes. The one-cell zygote divides as it moves along in the fallopian tube, where it continues to divide. Up until the 8-cell stage, each cell is totipotent. As the embryo travels along the oviduct, the cells continue to proliferate and the morula develops into a blastocyst that contains a cavity. The outer layer of cells of the blastocyst will go on to form the placenta and other supporting tissues needed for fetal development in the uterus.

The inner cell mass of cells located at the polarized end of the cavity contain the embryonic stem cells. These cells are of particular interest to researchers and others as they will eventually mature to form virtually all of the tissues in the human body.

These are images of blastocysts, caught on the head of a pin. In the picture on the right, the blastocyst is opened revealing the inner cell mass containing the stem cells.

What does pluripotent mean? What is important to know here is that while the inner cell mass cells can form virtually every type of cell found in the body, and therefore the cells are considered pluripotent, they cannot form an entire organism because they are unable to give rise to the placenta and other tissues necessary for gestational development in the uterus. This is a key point. Because their potential is not total, they are not totipotent only totipotent cells can go on to develop into a fetus. Pluripotent cells will form every cell in the body but will never form an embryo.

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Cells as the basic units of life The basis of stem cell biology begins with the understanding that cells form the basic units of life. In the 1600s, using his microscope, Robert Hooke observed small living compartments within cork plants. Likening the little units of cork tissue to miniature rooms or chambers, he coined the term "cells from the Latin word cella meaning a small room.

It took the scientific community two centuries to appreciate Hookes initial observations. By the mid 1800s, scientists such as Theodore Schwann began formulating the cellular theory of life which contained two major conclusions:

In 1908, at the Congress of the Hematologic Society in Berlin, Russian histologist Alexander Maksimov first proposed the term stem cell perhaps after noting that the stem of a tree gives rise to a variety of branches.

Cell specialization, for the 220 histologically different cell types characterized in the human body, is thus determined by the activation and suppression of a specific subset of the 20,000-25,000 genes representing 5% of the human genome. In addition, we are learning more about the role of the other 95% of the genome that has historically been referred to as junk DNA, which might not be junk after all (see Module 3 - Cellular differentiation to understand the newly discovered critical functions of junk DNA). (Wang, Huang et al.)

Self renewal is the ability of stem cells to divide indefinitely, producing a population of identical offspring. The concept of self-renewing stem cells originated in the 1960s with McCulloch and Till who demonstrated the presence of self-renewing cells in mouse bone marrow, which we now know are hematopoietic stem cells (Becker, Mc et al. 1963; Siminovitch, McCulloch et al. 1963). Today, cell surface markers and the expression of transcription factors are important characteristics of cellular differentiation.

Plasticity describes the capacity of stem cells to undergo an asymmetric division, cued by environmental conditions and genetic factors, to produce two dissimilar daughter cells. As of 2015, there is still controversy whether stem cells undergo symmetical or asymmetical division. In asymmetrical division, one daughter cell, identical to the parent,continues to contribute to the original stem cell line, while the other daughter cell differentiates into specialized cell types. Symmetrical division gives rises to two identical daughter cells that are either stem cells or cells that have begun to differentiate. Plasticity also describes the ability of an organism to change its phenotype in response to changes in the environment.

But not all stem cells exhibit these properties of self renewal and plasticity. While hematopoietic and embryonic stem cells exhibit these properties, other adult stem cells may only be committed to exhibit plasticity in their ability to differentiate into other types of cells.

The hallmark property of stem cells is their ability to differentiate into a wide variety of different cell types. Thus, scientists must demonstrate that the cells they have obtained are bona fide stem cells based on their capacity to differentiate into several other types of terminal or lineage progenitor cells.

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Pluripotent stem cells are found in the inner cell mass of the blastocyst and have the capacity to form any of the three germ layers that compose over 200 different cell types found in the body, excluding the placenta. Multipotent stem cells are derived from adult tissue, such as umbilical cord blood and bone marrow, and generally do not have the same capacity to differentiate into all the different cell types of the human body. Sources of stem cells Traditionally, there have been four primary tissue sources to obtain human stem cells: embryo, fetus, neonatal (including cord blood), and adult tissue. While most tissues and organs of the human body contain stem cells, their frequency varies from organ to organ. In circulating blood, for example, only 1:100,000 cells are stem cells, while the percentage of stem cells in bone marrow is much greater.

In addition, in the adult, most organs have a unique type of stem cell that can be identified by the specific cell surface markers it expresses.

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At the same time that Thomson reported his results, researchers from Johns Hopkins University, led by John Gearhart, described a method to isolate and culture immature germ cells from 5 to 8 week-old fetuses that were donated anonymously by women undergoing therapeutic or spontaneous abortions (Shamblott, Axelman et al. 1998). Dr. Gearhart and colleagues collected stem cells from the germinal centers of the ovaries or testes of the fetus and placed them in plastic dishes. They then added factors that enabled the germ stem cells to continue to divide, while simultaneously retaining them in a state of suspended development that prevented them from differentiating. These germ cell-derived stem cells could also be frozen, recovered, and maintained as stem cells in culture. Interestingly, Gearharts initial purpose for his research was merely to develop a tool for studying Downs syndrome.

The great advantage of deriving stem cells via iPS is that this remarkable technology does not require the destruction of human embryos. Moreover, the potential of iPS means that future stem cell therapies could be based on a patient's own cells (Takahashi and Yamanaka 2006). This is a key point since the use of ones own cells in stem cell therapy would eliminate the issue of tissue rejection, which is a critical problem in most organ donation scenarios. Tissue rejection would likely be an issue if patients were to receive stem cells from someone else. [insert religious views on the destruction of human embryos]

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Disadvantages of using embryonic stem cells The major disadvantages of embryonic stem cells, apart from ethical considerations, are that they may be rejected if transplanted into an HLA incompatible person, and more importantly, that they may form tumors more easily than adult-derived stem cells.

Advantages of using adult stem cells Most adult tissues contain multipotent stem cells. The most common source for multipotent stem cells is bone marrow. Bone marrow-derived stem cells in large measure generate the multiple cell types cells found in the blood. However, scientists can direct the differentiation process of bone marrow to differentiate into a variety of other cell types (Choi, Kurtz et al. 2011). Thus, there are considerable efforts undertaken to expand the ability of adult stem cells to differentiate into even more kinds of specialized cell types.

In addition, the ease with which bone marrow cells can be obtained, coupled with our experience using these cells in a variety of treatments (e.g., leukemia), have been a great impetus for further investigation of bone marrow as a source for adult stem cells.

While bone marrow-derived cells can differentiate into a variety of blood cells and other cell types, they are not as pluripotent as are embryonic stem cells. Nonetheless, there is a significant advantage to using bone marrow or any adult-derived stem cells in autologous therapy, as the risk of tissue rejection is avoided by using the patients own cells.

Disadvantages of using adult stem cells Adult derived stem cells, however, have some disadvantages in therapeutic applications. To date, disadvantages of adult stem cells are that they are:

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stemcellbioethics - Module 1 - The Biology of Stem Cells

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