You are here

Comment

Discuss

Potency Types

Stem cell potency specifies the ameliorative potential of the cell type.

Totipotent Stem Cells are produced from the fusion of an egg and sperm cell. Cells produced by the first few divisions of the fertilized egg cell are also Totipotent. These cells can differentiate into any type of cell without exception.

Pluripotent Stem Cells are the descendants of Totipotent cells and can differentiate into any cell type except for Totipotent Stem Cells.

Multipotent Stem Cells can produce only cells of a closely related family of cells (e.g. hematopoeietic Stem Cells differentiate into red blood cells, white blood cells, platelets etc.).

Unipotent cells can produce only one cell type, but have the property of self-renewal which distinguishes them from non-Stem Cells.

 

Stem Cells 101

 

What Are The Potential Uses Of Human Stem Cells And The Obstacles That Must Be Overcome Before These

There are many ways in which human stem cells can be used in basic research and in clinical research. However, there are many technical hurdles between the promise of stem cells and the realization of these uses, which will only be overcome by continued intensive stem cell research.

 

Studies of human embryonic stem cells may yield information about the complex events that occur during human development. A primary goal of this work is to identify how undifferentiated stem cells become differentiated. Scientists know that turning genes on and off is central to this process. Some of the most serious medical conditions, such as cancer and birth defects, are due to abnormal cell division and differentiation. A better understanding of the genetic and molecular controls of these processes may yield information about how such diseases arise and suggest new strategies for therapy. A significant hurdle to this use and most uses of stem cells is that scientists do not yet fully understand the signals that turn specific genes on and off to influence the differentiation of the stem cell.

Human stem cells could also be used to test new drugs. For example, new medications could be tested for safety on differentiated cells generated from human pluripotent cell lines. Other kinds of cell lines are already used in this way. Cancer cell lines, for example, are used to screen potential anti-tumor drugs. But, the availability of pluripotent stem cells would allow drug testing in a wider range of cell types. However, to screen drugs effectively, the conditions must be identical when comparing different drugs. Therefore, scientists will have to be able to precisely control the differentiation of stem cells into the specific cell type on which drugs will be tested. Current knowledge of the signals controlling differentiation fall well short of being able to mimic these conditions precisely to consistently have identical differentiated cells for each drug being tested.

Perhaps the most important potential application of human stem cells is the generation of cells and tissues that could be used for cell-based therapies. Today, donated organs and tissues are often used to replace ailing or destroyed tissue, but the need for transplantable tissues and organs far outweighs the available supply. Stem cells, directed to differentiate into specific cell types, offer the possibility of a renewable source of replacement cells and tissues to treat diseases including Parkinson's and Alzheimer's diseases, spinal cord injury, stroke, burns, heart disease, diabetes, osteoarthritis, and rheumatoid arthritis.

For example, it may become possible to generate healthy heart muscle cells in the laboratory and then transplant those cells into patients with chronic heart disease. Preliminary research in mice and other animals indicates that bone marrow stem cells, transplanted into a damaged heart, can generate heart muscle cells and successfully repopulate the heart tissue. Other recent studies in cell culture systems indicate that it may be possible to direct the differentiation of embryonic stem cells or adult bone marrow cells into heart muscle cells (Figure 4).

In people who suffer from type I diabetes, the cells of the pancreas that normally produce insulin are destroyed by the patient's own immune system. New studies indicate that it may be possible to direct the differentiation of human embryonic stem cells in cell culture to form insulin-producing cells that eventually could be used in transplantation therapy for diabetics.

To realize the promise of novel cell-based therapies for such pervasive and debilitating diseases, scientists must be able to easily and reproducibly manipulate stem cells so that they possess the necessary characteristics for successful differentiation, transplantation and engraftment. The following is a list of steps in successful cell-based treatments that scientists will have to learn to precisely control to bring such treatments to the clinic. To be useful for transplant purposes, stem cells must be reproducibly made to:

  • Proliferate extensively and generate sufficient quantities of tissue.

  • Differentiate into the desired cell type(s).

  • Survive in the recipient after transplant.

  • Integrate into the surrounding tissue after transplant.

  • Function appropriately for the duration of the recipient's life.

  • Avoid harming the recipient in any way.

Also, to avoid the problem of immune rejection, scientists are experimenting with different research strategies to generate tissues that will not be rejected.

To summarize, the promise of stem cell therapies is an exciting one, but significant technical hurdles remain that will only be overcome through years of intensive research.

 

Stem Cells 101

What Are The Similarities And Differences Between Embryonic And Adult Stem Cells?

Human embryonic and adult stem cells each have advantages and disadvantages regarding potential use for cell-based regenerative therapies. Of course, adult and embryonic stem cells differ in the number and type of differentiated cells types they can become. Embryonic stem cells can become all cell types of the body because they are pluripotent. Adult stem cells are generally limited to differentiating into different cell types of their tissue of origin. However, some evidence suggests that adult stem cell plasticity may exist, increasing the number of cell types a given adult stem cell can become.

 

Large numbers of embryonic stem cells can be relatively easily grown in culture, while adult stem cells are rare in mature tissues and methods for expanding their numbers in cell culture have not yet been worked out. This is an important distinction, as large numbers of cells are needed for stem cell replacement therapies.

A potential advantage of using stem cells from an adult is that the patient's own cells could be expanded in culture and then reintroduced into the patient. The use of the patient's own adult stem cells would mean that the cells would not be rejected by the immune system. This represents a significant advantage as immune rejection is a difficult problem that can only be circumvented with immunosuppressive drugs.

Embryonic stem cells from a donor introduced into a patient could cause transplant rejection. However, whether the recipient would reject donor embryonic stem cells has not been determined in human experiments.

 

Stem Cells 101

What Are Adult Stem Cells?

An adult stem cell is an undifferentiated cell found among differentiated cells in a tissue or organ, can renew itself, and can differentiate to yield 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. Some scientists now use the term somatic stem cell instead of adult stem cell. Unlike embryonic stem cells, which are defined by their origin (the inner cell mass of the blastocyst), the origin of adult stem cells in mature tissues is unknown.

 

Research on adult stem cells has recently 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 scientists to ask whether adult stem cells could be used for transplants. In fact, adult blood forming stem cells from bone marrow have been used in transplants for 30 years. Certain kinds of adult stem cells seem to have the ability to differentiate into a number of different cell types, given the right conditions. If this differentiation of adult stem cells can be controlled in the laboratory, these cells may become the basis of therapies for many serious common diseases.

The history of research on adult stem cells began about 40 years ago. In the 1960s, 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 Cells, was discovered a few years later. Stromal Cells are a mixed cell population that generates bone, cartilage, fat, and fibrous connective tissue.

Also in the 1960s, scientists who were studying rats discovered two regions of the brain that contained dividing cells, which become nerve cells. Despite these reports, most scientists believed that new nerve cells could not be generated in the adult brain. 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 types—astrocytes and oligodendrocytes, which are non-neuronal cells, and neurons, or nerve cells.

 

A. Where Are Adult Stem Cells Found And What Do They Normally Do?

adult stem cells have been identified in many organs and tissues. One important point to understand about adult stem cells is that there are a very small number of stem cells in each tissue. Stem cells are thought to reside in a specific area of each tissue where they may remain quiescent (non-dividing) for many years until they are activated by disease or tissue injury. The adult tissues reported to contain stem cells include brain, bone marrow, peripheral blood, blood vessels, skeletal muscle, skin and liver.

Scientists in many laboratories are trying to find ways to grow adult stem cells in cell culture and manipulate them to generate specific cell types so they can be used to treat injury or disease. Some examples of potential treatments include replacing the dopamine-producing cells in the brains of Parkinson's patients, developing insulin-producing cells for type I diabetes and repairing damaged heart muscle following a heart attack with cardiac muscle cells.

 

B. What tests are used for identifying adult stem cells?

Scientists do not agree on the criteria that should be used to identify and test adult stem cells. However, they often use one or more of the following three methods: (1) labeling the cells in a living tissue with molecular markers and then determining the specialized cell types they generate; (2) removing the cells from a living animal, labeling them in cell culture, and transplanting them back into another animal to determine whether the cells repopulate their tissue of origin; and (3) isolating the cells, growing them in cell culture, and manipulating them, often by adding growth factors or introducing new genes, to determine what differentiated cells types they can become.

Also, a single adult stem cell should be able to generate a line of genetically identical cells—known as a clone—which then gives rise to all the appropriate differentiated cell types of the tissue. Scientists tend to show either that a stem cell can give rise to a Clone of cells in cell culture, or that a purified population of candidate stem cells can repopulate the tissue after transplant into an animal. Recently, by infecting adult stem cells with a virus that gives a unique identifier to each individual cell, scientists have been able to demonstrate that individual adult stem cell clones have the ability to repopulate injured tissues in a living animal.

 

C. What Is Known About Adult Stem Cell Differentiation?

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. Adult stem cells may also exhibit the ability to form specialized cell types of other tissues, which is known as Transdifferentiation or plasticity.

Normal differentiation pathways of adult stem cells. In a living animal, adult stem cells can divide for a long period 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).

  • Hematopoietic stem cells give rise to all the types of blood cells: red blood cells, B lymphocytes, T lymphocytes, natural killer cells, neutrophils, basophils, eosinophils, monocytes, macrophages, and platelets.

  • Bone marrow stromal cells (Mesenchymal Stem Cells) give rise to a variety of cell types: bone cells (osteocytes), cartilage cells (chondrocytes), fat cells (adipocytes), and other kinds of connective tissue cells such as those in tendons.

  • neural stem cells in the brain give rise to its three major cell types: nerve cells (neurons) and two categories of non-neuronal cells—astrocytes and oligodendrocytes.

  • Epithelial stem cells in the lining of the digestive tract occur in deep crypts and give rise to several cell types: absorptive cells, goblet cells, Paneth cells, and enteroendocrine cells.

  • Skin stem cells occur in the basal layer of the epidermis and at the base of hair follicles. The epidermal stem cells give rise to keratinocytes, which migrate to the surface of the skin and form a protective layer. The follicular stem cells can give rise to both the hair follicle and to the epidermis.

Adult stem cell plasticity and transdifferentiation. A number of experiments have suggested that certain adult stem cell types are pluripotent. This ability to differentiate into multiple cell types is called plasticity or transdifferentiation. The following list offers examples of adult stem cell plasticity that have been reported during the past few years.

  • Hematopoietic stem cells may differentiate into: three major types of brain cells (neurons, oligodendrocytes, and astrocytes); skeletal muscle cells; cardiac muscle cells; and liver cells.

  • Bone marrow stromal cells may differentiate into: cardiac muscle cells and skeletal muscle cells.

  • Brain stem cells may differentiate into: blood cells and skeletal muscle cells.

Current research is aimed at determining the mechanisms that underlie adult stem cell plasticity. If such mechanisms can be identified and controlled, existing stem cells from a healthy tissue might be induced to repopulate and repair a diseased tissue (Figure 3).

 

D. What Are The Key Questions About Adult Stem Cells?

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

  • How many kinds of adult stem cells exist, and in which tissues do they exist?

  • What are the sources of adult stem cells in the body? Are they "leftover" embryonic stem cells, or do they arise in some other way? Why do they remain in an undifferentiated state when all the cells around them have differentiated?

  • Do adult stem cells normally exhibit plasticity, or do they only transdifferentiate when scientists manipulate them experimentally? What are the signals that regulate the proliferation and differentiation of stem cells that demonstrate plasticity?

  • Is it possible to manipulate adult stem cells to enhance their proliferation so that sufficient tissue for transplants can be produced?

  • Does a single type of stem cell exist—possibly in the bone marrow or circulating in the blood—that can generate the cells of any organ or tissue?

  • What are the factors that stimulate stem cells to relocate to sites of injury or damage?

Stem Cells 101

What Are The Unique Properties Of All Stem Cells?

Stem cells differ from other kinds of cells in the body. All stem cells—regardless of their source—have three general properties: they are capable of dividing and renewing themselves for long periods; they are unspecialized; and they can give rise to specialized cell types.

 

Scientists are trying to understand two fundamental properties of stem cells that relate to their Long-Term Self-Renewal:

  1. why can embryonic stem cells proliferate for a year or more in the laboratory without differentiating, but most adult stem cells cannot; and

  2. what are the factors in living organisms that normally regulate stem cell Proliferation and self-renewal?

Discovering the answers to these questions may make it possible to understand how cell proliferation is regulated during normal embryonic development or during the abnormal cell division that leads to cancer. Importantly, such information would enable scientists to grow embryonic and adult stem cells more efficiently in the laboratory.

Stem cells are unspecialized. One of the fundamental properties of a stem cell is that it does not have any tissue-specific structures that allow it to perform specialized functions. A stem cell cannot work with its neighbors to pump blood through the body (like a heart muscle cell); it cannot carry molecules of oxygen through the bloodstream (like a red blood cell); and it cannot fire electrochemical signals to other cells that allow the body to move or speak (like a nerve cell). However, unspecialized stem cells can give rise to specialized cells, including heart muscle cells, blood cells, or nerve cells.

Stem cells are capable of dividing and renewing themselves for long periods. Unlike muscle cells, blood cells, or nerve cells—which do not normally replicate themselves—stem cells may replicate many times. When cells replicate themselves many times over it is called proliferation. A starting population of stem cells that proliferates for many months in the laboratory can yield millions of cells. If the resulting cells continue to be unspecialized, like the parent stem cells, the cells are said to be capable of long-term self-renewal.

The specific factors and conditions that allow stem cells to remain unspecialized are of great interest to scientists. It has taken scientists many years of trial and error to learn to grow stem cells in the laboratory without them spontaneously differentiating into specific cell types. For example, it took 20 years to learn how to grow human embryonic stem cells in the laboratory following the development of conditions for growing mouse stem cells. Therefore, an important area of research is understanding the signals in a mature organism that cause a stem cell population to proliferate and remain unspecialized until the cells are needed for repair of a specific tissue. Such information is critical for scientists to be able to grow large numbers of unspecialized stem cells in the laboratory for further experimentation.

Stem cells can give rise to specialized cells. When unspecialized stem cells give rise to specialized cells, the process is called Differentiation. Scientists are just beginning to understand the signals inside and outside cells that trigger stem cell differentiation. The internal signals are controlled by a cell's genes, which are interspersed across long strands of DNA, and carry coded instructions for all the structures and functions of a cell. The external signals for cell differentiation include chemicals secreted by other cells, physical contact with neighboring cells, and certain molecules in the Microenvironment.

Therefore, many questions about stem cell differentiation remain. For example, are the internal and external signals for cell differentiation similar for all kinds of stem cells? Can specific sets of signals be identified that promote differentiation into specific cell types? Addressing these questions is critical because the answers may lead scientists to find new ways of controlling stem cell differentiation in the laboratory, thereby growing cells or tissues that can be used for specific purposes including cell-based therapies.

Adult stem cells typically generate the cell types of the tissue in which they reside. A blood-forming adult stem cell in the bone marrow, for example, normally gives rise to the many types of blood cells such as red blood cells, white blood cells and platelets. Until recently, it had been thought that a blood-forming cell in the bone marrow—which is called a hematopoietic stem cell—could not give rise to the cells of a very different tissue, such as nerve cells in the brain. However, a number of experiments over the last several years have raised the possibility that stem cells from one tissue may be able to give rise to cell types of a completely different tissue, a phenomenon known as Plasticity. Examples of such plasticity include blood cells becoming neurons, liver cells that can be made to produce insulin, and Hematopoietic Stem Cells that can develop into heart muscle. Therefore, exploring the possibility of using adult stem cells for cell-based therapies has become a very active area of investigation by researchers.

* Page citation: Stem Cell Basics: What are the unique properties of all stem cells? . In Stem Cell Information [World Wide Web site]. Bethesda, MD: National Institutes of Health, U.S. Department of Health and Human Services, 2006

 

Stem Cells 101

 

What Are Embryonic Stem Cells?

A. What Stages Of Early Embryonic Development Are Important For Generating Embryonic Stem Cells?

Embryonic stem cells, as their name suggests, are derived from embryos. Specifically, embryonic stem cells are derived from embryos that develop from eggs that have been fertilized in vitro—in an In Vitro Fertilization clinic—and then donated for research purposes with informed consent of the donors. They are not derived from eggs fertilized in a woman's body. The embryos from which human embryonic stem cells are derived are typically four or five days old and are a hollow microscopic ball of cells called the blastocyst. The blastocyst includes three structures: the Trophoblast, which is the layer of cells that surrounds the blastocyst; the Blastocoel, which is the hollow cavity inside the blastocyst; and the inner cell mass, which is a group of approximately 30 cells at one end of the blastocoel.

 

B. How Are Embryonic Stem Cells Grown In The Laboratory?

Growing cells in the laboratory is known as Cell Culture. Human embryonic stem cells are isolated by transferring the inner cell mass into a plastic laboratory culture dish that contains a nutrient broth known as Culture Medium. The cells divide and spread over the surface of the dish. The inner surface of the culture dish is typically coated with mouse embryonic skin cells that have been treated so they will not divide. This coating layer of cells is called a Feeder Layer. The reason for having the mouse cells in the bottom of the culture dish is to give the inner cell mass cells a sticky surface to which they can attach. Also, the feeder cells release nutrients into the culture medium. Recently, scientists have begun to devise ways of growing embryonic stem cells without the mouse feeder cells. This is a significant scientific advancement because of the risk that viruses or other macromolecules in the mouse cells may be transmitted to the human cells.

Over the course of several days, the cells of the inner cell mass proliferate and begin to crowd the culture dish. When this occurs, they are removed gently and plated into several fresh culture dishes. The process of replating the cells is repeated many times and for many months, and is called Subculturing. Each cycle of subculturing the cells is referred to as a Passage. After six months or more, the original 30 cells of the inner cell mass yield millions of embryonic stem cells. Embryonic stem cells that have proliferated in cell culture for six or more months without differentiating, are Pluripotent, and appear genetically normal are referred to as an Embryonic Stem Cell Line.

Once cell lines are established, or even before that stage, batches of them can be frozen and shipped to other laboratories for further culture and experimentation.

 

C. What Laboratory Tests Are Used To Identify Embryonic Stem Cells?

At various points during the process of generating embryonic stem cell lines, scientists test the cells to see whether they exhibit the fundamental properties that make them embryonic stem cells. This process is called characterization.

As yet, scientists who study human embryonic stem cells have not agreed on a standard battery of tests that measure the cells' fundamental properties. Also, scientists acknowledge that many of the tests they do use may not be good indicators of the cells' most important biological properties and functions. Nevertheless, laboratories that grow human embryonic stem cell lines use several kinds of tests. These tests include:

  • growing and subculturing the stem cells for many months. This ensures that the cells are capable of long-term self-renewal. Scientists inspect the cultures through a microscope to see that the cells look healthy and remain Undifferentiated.

  • using specific techniques to determine the presence of Surface Markers that are found only on undifferentiated cells. Another important test is for the presence of a protein called Oct-4, which undifferentiated cells typically make. Oct-4 is a transcription factor, meaning that it helps turn genes on and off at the right time, which is an important part of the processes of cell differentiation and embryonic development.

  • examining the chromosomes under a microscope. This is a method to assess whether the chromosomes are damaged or if the number of chromosomes has changed. It does not detect genetic mutations in the cells.

  • determining whether the cells can be subcultured after freezing, thawing, and replating.

  • testing whether the human embryonic stem cells are pluripotent by 1) allowing the cells to differentiate spontaneously in cell culture; 2) manipulating the cells so they will differentiate to form specific cell types; or 3) injecting the cells into an immunosuppressed mouse to test for the formation of a benign tumor called a Teratoma. Teratomas typically contain a mixture of many differentiated or partly differentiated cell types—an indication that the embryonic stem cells are capable of differentiating into multiple cell types.

D. How Are Embryonic Stem Cells Stimulated To Differentiate?

As long as the embryonic stem cells in culture are grown under certain conditions, they can remain undifferentiated (unspecialized). But if cells are allowed to clump together to form Embryoid Bodies, they begin to differentiate spontaneously. They can form muscle cells, nerve cells, and many other cell types. Although spontaneous differentiation is a good indication that a culture of embryonic stem cells is healthy, it is not an efficient way to produce cultures of specific cell types.

So, to generate cultures of specific types of differentiated cells—heart muscle cells, blood cells, or nerve cells, for example—scientists try to control the differentiation of embryonic stem cells. They change the chemical composition of the culture medium, alter the surface of the culture dish, or modify the cells by inserting specific genes. Through years of experimentation scientists have established some basic protocols or "recipes" for the Directed Differentiation of embryonic stem cells into some specific cell types (Figure 1). (For more examples of directed differentiation of embryonic stem cells, see Chapters 5–9 and Appendices B and C of the NIH report Stem Cells: Scientific Progress and Future Research Directions.)

If scientists can reliably direct the differentiation of embryonic stem cells into specific cell types, they may be able to use the resulting, differentiated cells to treat certain diseases at some point in the future. Diseases that might be treated by transplanting cells generated from human embryonic stem cells include Parkinson's disease, diabetes, traumatic spinal cord injury, Purkinje cell degeneration, Duchenne's muscular dystrophy, heart disease, and vision and hearing loss.

 

Stem Cells 101

 

What Are Stem Cells And Why Are They Important?

Stem Cells for the Future Treatment of Parkinson's Disease

 

Parkinson's disease (PD) is a very common neurodegenerative disorder that affects more than 2% of the population over 65 years of age. PD is caused by a progressive degeneration and loss of dopamine (DA)-producing neurons, which leads to tremor, rigidity, and hypokinesia (abnormally decreased mobility). It is thought that PD may be the first disease to be amenable to treatment using stem cell transplantation. Factors that support this notion include the knowledge of the specific cell type (DA neurons) needed to relieve the symptoms of the disease. In addition, several laboratories have been successful in developing methods to induce embryonic stem cells to differentiate into cells with many of the functions of DA neurons.

 

In a recent study, scientists directed mouse embryonic stem cells to differentiate into DA neurons by introducing the gene Nurr1. When transplanted into the brains of a rat model of PD, these stem cell-derived DA neurons reinnervated the brains of the rat Parkinson model, released dopamine and improved motor function.

Regarding human stem cell therapy, scientists are developing a number of strategies for producing dopamine neurons from human stem cells in the laboratory for transplantation into humans with Parkinson's disease. The successful generation of an unlimited supply of dopamine neurons could make neurotransplantation widely available for Parkinson's patients at some point in the future.

Stem cells have two important characteristics that distinguish them from other types of cells. First, they are unspecialized cells that renew themselves for long periods through cell division. The second is that under certain physiologic or experimental conditions, they can be induced to become cells with special functions such as the beating cells of the heart muscle or the insulin-producing cells of the pancreas.

Scientists primarily work with two kinds of stem cells from animals and humans: embryonic stem cells and adult stem cells, which have different functions and characteristics that will be explained in this document. Scientists discovered ways to obtain or derive stem cells from early mouse embryos more than 20 years ago. Many years of detailed study of the biology of mouse stem cells led to the discovery, in 1998, of how to isolate stem cells from human embryos and grow the cells in the laboratory. These are called human embryonic stem cells. The embryos used in these studies were created for infertility purposes through in vitro fertilization procedures and when they were no longer needed for that purpose, they were donated for research with the informed consent of the donor.

Stem cells are important for living organisms for many reasons. In the 3- to 5-day-old embryo, called a blastocyst, stem cells in developing tissues give rise to the multiple specialized cell types that make up the heart, lung, skin, 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.

It has been hypothesized by scientists that stem cells may, at some point in the future, become the basis for treating diseases such as Parkinson's disease, diabetes, and heart disease.

Scientists want to study stem cells in the laboratory so they can learn about their essential properties and what makes them different from specialized cell types. As scientists learn more about stem cells, it may become possible to use the cells not just in cell-based therapies, but also for screening new drugs and toxins and understanding birth defects. However, as mentioned above, human embryonic stem cells have only been studied since 1998. Therefore, in order to develop such treatments scientists are intensively studying the fundamental properties of stem cells, which include:

  1. determining precisely how stem cells remain unspecialized and self renewing for many years; and

  2. identifying the signals that cause stem cells to become specialized cells

Stem Cells 101

Introduction

Research on stem cells is advancing knowledge about how an organism develops from a single cell and how healthy cells replace damaged cells in adult organisms. This promising area of science is also leading scientists to investigate the possibility of cell-based therapies to treat disease, which is often referred to as regenerative or reparative medicine.

Stem cells are one of the most fascinating areas of biology today. But like many expanding fields of scientific inquiry, research on stem cells raises scientific questions as rapidly as it generates new discoveries.

The NIH developed this primer to help readers understand the answers to questions such as: What are stem cells? What different types of stem cells are there and where do they come from? What is the potential for new medical treatments using stem cells? What research is needed to make such treatments a reality?

 

Stem Cells 101

 

References: What is an Adult Stem Cell?

Below are the references for the series of articles about What is an Adult Stem Cell?

 

  1. Akashi, K., Traver, D., Kondo, M., and Weissman, I.L. (1999). Lymphoid development from hematopoietic stem cells. Int. J. Hematol. 69, 217–226.

  2. Akashi, K., Kondo, M., Cheshier, S., Shizuru, J., Gandy, K., Domen, J., Mebius, R., Traver, D., and Weissman, I.L. (1999). Lymphoid development from stem cells and the common lymphocyte progenitors. Cold Spring Harb. Symp. Quant. Biol. 64,

    1–12.

  3. Akashi, K., Traver, D., Miyamoto, T., and Weissman, I.L. (2000). A clonogenic common myeloid progenitor that gives rise to all myeloid lineages. Nature. 404, 193–197.

  4. Alison, M.R., Poulsom, R., Jeffery, R., Dhillon, A.P., Quaglia, A., Jacob, J., Novelli, M., Prentice, G., Williamson, J., and Wright, N.A. (2000). Hepatocytes from non-hepatic adult stem cells. Nature. 406, 257.

  5. Altman, J. and Das, G.D. (1965). Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J. Comp. Neurol. 124, 319–335.

  6. Altman, J. (1969). Autoradiographic and histological studies of postnatal neurogenesis. IV. Cell proliferation and migration in the anterior forebrain, with special reference to persisting neurogenesis in the olfactory bulb. J. Comp. Neurol. 137, 433–457.

  7. Anderson, D.J., Gage, F.H., and Weissman, I.L. (2001). Can stem cells cross lineage boundaries? Nat. Med. 7, 393–395.

  8. Asahara, T., Murohara, T., Sullivan, A., Silver, M., van der Zee R., Li, T., Witzenbichler, B., Schatteman, G., and Isner, J.M. (1997). Isolation of putative progenitor endothelial cells for angiogenesis. Science. 275, 964–967.

  9. Becker, A.J., McCullough, E.A., and Till, J.E. (1963). Cytological demonstration of the clonal nature of spleen colonies derived from transplanted mouse marrow cells. Nature. 197, 452–454.

  10. Bianco, P. and Cossu, G. (1999). Uno, nessuno e centomila: searching for the identity of mesodermal progenitors. Exp. Cell Res. 251, 257–263.

  11. Bianco, P., Riminucci, M., Kuznetsov, S., and Robey, P.G. (1999). Multipotential cells in the bone marrow stroma: regulation in the context of organ physiology. Crit. Rev. Eukaryotic. Gene Expr. 9, 159–173.

  12. Bianco, P., Riminucci, M., Gronthos, S., and Robey, P.G. (2001). Bone marrow stromal stem cells: nature, biology, and potential applications. Stem Cells. 19, 180–192.

  13. Bjornson, C.R., Rietze, R.L., Reynolds, B.A., Magli, M.C., and Vescovi, A.L. (1999). Turning brain into blood: a hematopoietic fate adopted by adult neural stem cells in vivo. Science. 283, 534–537.

  14. Blau, H., personal communication.

  15. Brazelton, T.R., Rossi, F.M., Keshet, G.I., and Blau, H.M. (2000). From marrow to brain: expression of neuronal phenotypes in adult mice. Science. 290, 1775–1779.

  16. Bruder, S.P., Jaiswal, N., and Haynesworth, S.E. (1997). Growth kinetics, self-renewal, and the osteogenic potential of purified human mesenchymal stem cells during extensive subcultivation and following cryopreservation. J. Cell. Biochem. 64,

    278–294.

  17. Clarke, D.L., Johansson, C.B., Wilbertz, J., Veress, B., Nilsson, E., Karlström, H., Lendahl, U., and Frisen, J. (2000). Generalized potential of adult neural stem cells. Science. 288, 1660–1663.

  18. Crosby, H.A. and Strain, A.J. (2001). Adult liver stem cells: bone marrow, blood, or liver derived? Gut. 48, 153–154.

  19. Dabeva, M.D. and Shafritz, D.A. (1993). Activation, proliferation, and differentiation of progenitor cells into hepatocytes in the D-galactosamine model of liver regeneration. Am. J. Pathol. 143, 1606–1620.

  20. Davis, A.A. and Temple, S. (1994). A self-renewing multipotential stem cell in embryonic rat cerebral cortex. Nature. 372,

    263–266.

  21. De Angelis, L., Berghella, L., Coletta, M., Lattanzi, L., Zanchi, M., Cusella-De Angelis, M.G., Ponzetto, C., and Cossu, G. (1999). Skeletal myogenic progenitors originating from embryonic dorsal aorta coexpress endothelial and myogenic markers and contribute to postnatal muscle growth and regeneration. J. Cell Biol. 147, 869–877.

  22. Del Bigio, M.R. (1995). The ependyma: a protective barrier between brain and cerebrospinal fluid. Glia. 14, 1–13.

  23. Deutsch, G., Jung, J., Zheng, M., Lora, J., and Zaret, K.S. (2001). A bipotential precursor population for pancreas and liver within the embryonic endoderm. Development. 128, 871–881.

  24. Doetsch, F., Garcia-Verdugo, J.M., and Alvarez-Buylla, A. (1997). Cellular composition and three-dimensional organization of the subventricular germinal zone in the adult mammalian brain. J. Neurosci. 17, 5046–5061.

  25. Doetsch, F., Caille, I., Lim, D.A., Garcia-Verdugo, J.M., and Alvarez-Buylla, A. (1999). Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell. 97, 703–716.

  26. Domen, J. and Weissman, I.L. (1999). Self-renewal, differentiation or death: regulation and manipulation of hematopoietic stem cell fate. Mol. Med. Today. 5, 201–208.

  27. Eriksson, P.S., Perfilieva, E., Bjork-Eriksson, T., Alborn, A.M., Nordborg, C., Peterson, D.A., and Gage, F.H. (1998). Neurogenesis in the adult human hippocampus. Nat. Med. 4, 1313–1317.

  28. Ferrari, G., Cusella-De Angelis, G., Coletta, M., Paolucci, E., Stornaiuolo, A., Cossu, G., and Mavilio, F. (1998). Muscle regeneration by bone marrow-derived myogenic progenitors. Science. 279, 1528–1530.

  29. Folkman, J. (1998). Therapeutic angiogenesis in ischemic limbs. Circulation. 97, 1108–1110.

  30. Friedenstein, A.J., Piatetzky-Shapiro, I.I., and Petrakova, K.V. (1966). Osteogenesis in transplants of bone marrow cells. J. Embryol. Exp. Morphol. 16, 381–390.

  31. Friedenstein, A.J., Petrakova, K.V., Kurolesova, A.I., and Frolova, G.P. (1968). Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation. 6, 230–247.

  32. Friedenstein, A.J., Chailakhjan, R.K., and Lalykina, K.S. (1970). The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell Tissue Kinet. 3, 393–403.

  33. Gage, F., personal communication.

  34. Gage, F.H., Ray, J., and Fisher, L.J. (1995). Isolation, characterization, and use of stem cells from the CNS. Annu. Rev. Neurosci. 18, 159–192.

  35. Gage, F.H., Coates, P.W., Palmer, T.D., Kuhn, H.G., Fisher, L.J., Suhonen, J.O., Peterson, D.A., Suhr, S.T., and Ray, J. (1995). Survival and differentiation of adult neuronal progenitor cells transplanted to the adult brain. Proc. Natl. Acad. Sci. U. S. A. 92, 11879–11883.

  36. Gandarillas, A. and Watt, F.M. (1997). c-Myc promotes differentiation of human epidermal stem cells. Genes Dev. 11,

    2869–2882.

  37. Germain, L., Noel, M., Gourdeau, H., and Marceau, N. (1988). Promotion of growth and differentiation of rat ductular oval cells in primary culture. Cancer Res. 48, 368–378.

  38. Geschwind, D.H., Ou, J., Easterday, M.C., Dougherty, J.D., Jackson, R.L., Chen, Z., Antoine, H., Terskikh, A., Weissman, I.L., Nelson, S.F., and Kornblum, H.I. (2001). A genetic analysis of neural progenitor differentiation. Neuron. 29, 325–339.

  39. Ghazizadeh, S. and Taichman, L.B. (2001). Multiple classes of stem cells in cutaneous epithelium: a lineage analysis of adult mouse skin. EMBO J. 20, 1215–1222.

  40. Gordon, M.Y., Riley, G.P., Watt, S.M., and Greaves, M.F. (1987). Compartmentalization of a haematopoietic growth factor (GM-CSF) by glycosaminoglycans in the bone marrow Microenvironment. Nature. 326, 403–405.

  41. Gritti, A., Parati, E.A., Cova, L., Frolichsthal, P., Galli, R., Wanke, E., Faravelli, L., Morassutti, D.J., Roisen, F., Nickel, D.D., and Vescovi, A.L. (1996). Multipotential stem cells from the adult mouse brain proliferate and self-renew in response to basic fibroblast growth factor. J. Neurosci. 16, 1091–1100.

  42. Guenechea, G., Gan, O.I., Dorrell, C., and Dick, J.E. (2001). Distinct classes of human stem cells that differ in proliferative and self-renewal potential. Nat. Immunol. 2, 75–82.

  43. Gussoni, E., Soneoka, Y., Strickland, C.D., Buzney, E.A., Khan, M.K., Flint, A.F., Kunkel, L.M., and Mulligan, R.C. (1999). Dystrophin expression in the mdx mouse restored by stem cell transplantation. Nature. 401, 390–394.

  44. Holtzer, H. (1978). Cell lineages, stem cells and the ‘quantal' cell cycle concept. In: Stem cells and tissue homeostasis. Eds: B.I. Lord, C.S. Potten, and R.J. Cole. (Cambridge, New York: Cambridge University Press). 1–28.

  45. Hunt, P., Robertson, D., Weiss, D., Rennick, D., Lee, F., and Witte, O.N. (1987). A single bone marrow-derived stromal cell type supports the in vitro growth of early lymphoid and myeloid cells. Cell. 48, 997–1007.

  46. Jackson, K., Majka SM, Wang H, Pocius J, Hartley CJ, Majesky MW, Entman ML, Michael LH, Hirschi KK, and Goodell MA (2001). Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. J. Clin. Invest. 107, 1–8.

  47. Johansson, C.B., Momma, S., Clarke, D.L., Risling, M., Lendahl, U., and Frisen, J. (1999). Identification of a neural stem cell in the adult mammalian central nervous system. Cell. 96, 25–34.

  48. Johe, K.K., Hazel, T.G., Muller, T., Dugich-Djordjevic, M.M., and McKay, R.D. (1996). Single factors direct the differentiation of stem cells from the fetal and adult central nervous system. Genes Dev. 10, 3129–3140.

  49. Kalka, C., Masuda, H., Takahashi, T., Kalka-Moll, W.M., Silver, M., Kearney, M., Li, T., Isner, J.M., and Asahara, T. (2000). Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization. Proc. Natl. Acad. Sci. U. S. A. 97, 3422–3427.

  50. Keller, G. (2001). The hemangioblast. Marshak, D.R., Gardner, D.K., and Gottlieb, D. eds. (Cold Spring Harbor, New York: Cold Spring Harbor Laboratory Press). 329–348.

  51. Kocher, A.A., Schuster, M.D., Szabolcs, M.J., Takuma, S., Burkhoff, D., Wang, J., Homma, S., Edwards, N.M., and Itescu, S. (2001). Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat. Med. 7, 430–436.

  52. Krause, D.S., Theise, N.D., Collector, M.I., Henegariu, O., Hwang, S., Gardner, R., Neutzel, S., and Sharkis, S.J. (2001). Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell. 105, 369–377.

  53. Kuznetsov, S.A., Mankani, M.H., Gronthos, S., Satomura, K., Bianco, P., and Robey P.G. (2001). Circulating skeletal stem cells. J. Cell Biol. 153, 1133–1140.

  54. Lagasse, E., Connors, H., Al Dhalimy, M., Reitsma, M., Dohse, M., Osborne, L., Wang, X., Finegold, M., Weissman, I.L., and Grompe, M. (2000). Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nat. Med. 6, 1229–1234.

  55. Lazaro, C.A., Rhim, J.A., Yamada, Y., and Fausto, N. (1998). Generation of hepatocytes from oval cell precursors in culture. Cancer Res. 58, 5514–5522.

  56. Le Douarin, N.M. (1980). The ontogeny of the neural crest in avian embryo chimaeras. Nature. 286, 663–669.

  57. Le Douarin, N.M. and Kalcheim, C. (1999). The migration of neural crest cells. In: The neural crest. (Cambridge, New York: Cambridge University Press). 23–59.

  58. Leblond, C.P. (1964). Classification of cell populations on the basis of their proliferative behavior. National Cancer Institute. 14, 119–150.

  59. Lois, C. and Alvarez-Buylla, A. (1994). Long-distance neuronal migration in the adult mammalian brain. Science. 264,

    1145–1148.

  60. Lumelsky, N., Blondel, O., Laeng, P., Velasco, I., Ravin, R., and McKay, R. (2001). Differentiation of Embryonic Stem Cells to Insulin-Secreting Structures Similiar to Pancreatic Islets. Science. 292, 1309–1599.

  61. Luskin, M.B. (1993). Restricted proliferation and migration of postnatally generated neurons derived from the forebrain subventricular zone. Neuron. 11, 173–189.

  62. Mauro, A. (1961). Satellite cell of skeletal muscle fibers. J. Biophys. Biochem. Cytol. 9, 493–495.

  63. McKay, R. (1997). Stem cells in the central nervous system. Science. 276, 66–71.

  64. McKay, R., personal communication.

  65. Mezey, E., Chandross, K.J., Harta, G., Maki, R.A., and McKercher, S.R. (2000). Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow. Science. 290, 1779–1782.

  66. Momma, S., Johansson, C.B., and Frisen, J. (2000). Get to know your stem cells. Curr. Opin. Neurobiol. 10, 45–49.

  67. Morrison, S.J., White, P.M., Zock, C., and Anderson, D.J. (1999). Prospective identification, isolation by flow cytometry, and in vivo self-renewal of Multipotent mammalian neural crest stem cells. Cell. 96, 737–749.

  68. Morrison, S.J. (2001). Neuronal differentiation: Proneural genes inhibit gliogenesis. Curr. Biol. 11, R349-R351.

  69. Morshead, C.M., Reynolds, B.A., Craig, C.G., McBurney, M.W., Staines, W.A., Morassutti, D., Weiss, S., and van der, K.D. (1994). Neural stem cells in the adult mammalian forebrain: a relatively quiescent subpopulation of subependymal cells. Neuron. 13, 1071–1082.

  70. Morshead, C.M. and van der Kooy, K.D. (2001). A new ‘spin' on neural stem cells? Curr. Opin. Neurobiol. 11, 59–65.

  71. Orlic, D., Kajstura, J., Chimenti, S., Jakoniuk, I., Anderson, S.M., Li, B., Pickel, J., McKay, R., Nadal-Ginard, B., Bodine, D.M., Leri, A., and Anversa, P. (2001). Bone marrow cells regenerate infarcted myocardium. Nature. 410, 701–705.

  72. Osawa, M., Hanada, K., Hamada, H., and Nakauchi, H. (1996). Long-term lymphohematopoietic reconstitution by a single CD34- low/negative hematopoietic stem cell. Science. 273, 242–245.

  73. Owen, M. (1988). Marrow derived stromal stem cells. J. Cell Science Supp. 10, 63–76.

  74. Palmer, T.D., Takahashi, J., and Gage, F.H. (1997). The adult rat hippocampus contains primordial neural stem cells. Mol. Cell. Neurosci. 8, 389–404.

  75. Palmer, T.D., Willhoite, A.R., and Gage, F.H. (2000). Vascular niche for adult hippocampal neurogenesis. J. Comp. Neurol. 425, 479–494.

  76. Panicker, M. and Rao, M. (2001). Stem cells and neurogenesis. Marshak, D.R., Gardner, D.K., and Gottlieb, D. eds. (Cold Spring Harbor, New York: Cold Spring Harbor Laboratory Press). 399–438.

  77. Petersen, B.E., Bowen, W.C., Patrene, K.D., Mars, W.M., Sullivan, A.K., Murase, N., Boggs, S.S., Greenberger, J.S., and Goff, J.P. (1999). Bone marrow as a potential source of hepatic oval cells. Science. 284, 1168–1170.

  78. Pittenger, M.F. and Marshak, D.R. (2001). Mesenchymal stem cells of human adult bone marrow. Marshak, D.R., Gardner, D.K., and Gottlieb, D. eds. (Cold Spring Harbor, New York: Cold Spring Harbor Laboratory Press). 349–374.

  79. Poole, T.J., Finkelstein, E.B., and Cox, C.M. (2001). The role of FGF and VEGF in angioblast induction and migration during vascular development. Dev. Dyn. 220, 1–17.

  80. Reynolds, B.A. and Weiss, S. (1992). Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science. 255, 1707–1710.

  81. Roberts, R., Gallagher, J., Spooncer, E., Allen, T.D., Bloomfield, F., and Dexter, T.M. (1988). Heparan sulphate bound growth factors: a mechanism for stromal cell mediated haemopoiesis. Nature. 332, 376–378.

  82. Robey, P.G. (2000). Stem cells near the century mark. J. Clin. Invest. 105, 1489–1491.

  83. Roy, V. and Verfaillie, C.M. (1999). Expression and function of cell adhesion molecules on fetal liver, cord blood and bone marrow hematopoietic progenitors: implications for anatomical localization and developmental stage specific regulation of hematopoiesis. Exp. Hematol. 27, 302–312.

  84. Schultz, E. (1976). Fine structure of satellite cells in growing skeletal muscle. Am. J. Anat. 147, 49–70.

  85. Schultz, E. (1996). Satellite cell proliferative compartments in growing skeletal muscles. Dev. Biol. 175, 84–94.

  86. Seale, P. and Rudnicki, M.A. (2000). A new look at the origin, function, and "stem-cell" status of muscle satellite cells. Dev. Biol. 218, 115–124.

  87. Sell, S. (1990). Is there a liver stem cell? Cancer Res. 50, 3811–3815.

  88. Shalaby, F., Rossant, J., Yamaguchi, T.P., Gertsenstein, M., Wu, X.F., Breitman, M.L., and Schuh, A.C. (1995). Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature. 376, 62–66.

  89. Shi, Q., Rafii, S., Wu, M.H., Wijelath, E.S., Yu, C., Ishida, A., Fujita, Y., Kothari, S., Mohle, R., Sauvage, L.R., Moore, M.A., Storb, R.F., and Hammond, W.P. (1998). Evidence for circulating bone marrow-derived endothelial cells. Blood. 92, 362–367.

  90. Shihabuddin, L.S., Palmer, T.D., and Gage, F.H. (1999). The search for neural progenitor cells: prospects for the therapy of neurodegenerative disease. Mol. Med. Today. 5, 474–480.

  91. Sieber-Blum, M. (2000). Factors controlling lineage specification in the neural crest. Int. Rev. Cytol. 197, 1–33.

  92. Sirica, A.E., Mathis, G.A., Sano, N., and Elmore, L.W. (1990). Isolation, culture, and transplantation of intrahepatic biliary epithelial cells and oval cells. Pathobiology. 58, 44–64.

  93. Slack, J.M. (2000). Stem Cells in Epithelial Tissues. Science. 287, 1431–1433.

  94. Takahashi, T., Kalka, C., Masuda, H., Chen, D., Silver, M., Kearney, M., Magner, M., Isner, J.M., and Asahara, T. (1999). Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Nat. Med. 5, 434–438.

  95. Taylor, G., Lehrer, M.S., Jensen, P.J., Sun, T.T., and Lavker, R.M. (2000). Involvement of follicular stem cells in formingnot only the follicle but also the epidermis. Cell. 102, 451–461.

  96. Temple, S. and Alvarez-Buylla, A. (1999). Stem cells in the adult mammalian central nervous system. Curr. Opin. Neurobiol. 9, 135–141.

  97. Theise, N.D., Nimmakayalu, M., Gardner, R., Illei, P.B., Morgan, G., Teperman, L., Henegariu, O., and Krause, D.S. (2000). Liver from bone marrow in humans. Hepatology. 32, 11–16.

  98. Thorgeirsson, S.S. (1993). Hepatic stem cells. Am. J. Pathol. 142, 1331–1333.

  99. Till, J.E. and McCullough, E.A. (1961). A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat. Res. 14, 213–222.

  100. Tropepe, V., Sibilia, M., Ciruna, B.G., Rossant, J., Wagner, E.F., and van der Kooy D. (1999). Distinct neural stem cells proliferate in response to EGF and FGF in the developing mouse telencephalon. Dev. Biol. 208, 166–188.

  101. Verfaillie, C.M. (1998). Adhesion receptors as regulators of the hematopoietic process. Blood. 92, 2609–2612.

  102. Vescovi, A.L., Reynolds, B.A., Fraser, D.D., and Weiss, S. (1993). bFGF regulates the proliferative fate of unipotent (neuronal) and bipotent (neuronal/astroglial) EGF-generated CNS progenitor cells. Neuron. 11, 951–966.

  103. Vescovi, A.L., Gritti, A., Galli, R., and Parati, E.A. (1999). Isolation and intracerebral grafting of nontransformed multipotential embryonic human CNS stem cells. J. Neurotrauma. 16, 689–693.

  104. Weiss, S. and van der Kooy D. (1998). CNS stem cells: where's the biology (a.k.a. beef)? J. Neurobiol. 36, 307–314.

  105. Weissman, I.L. (2000). Stem cells: units of development, units of regeneration, and units in evolution. Cell. 100, 157–168.

  106. White, P.M., Morrison, S.J., Orimoto, K., Kubu, C.J., Verdi, J.M., and Anderson, D.J. (2001). Neural crest stem cells undergo cell-intrinsic developmental changes in sensitivity to instructive differentiation signals. Neuron. 29, 57–71.

  107. Whitlock, C.A., Tidmarsh, G.F., Muller-Sieburg, C., and Weissman, I.L. (1987). Bone marrow stromal cell lines with lymphopoietic activity express high levels of a pre-B neo-plasia-associated molecule. Cell. 48, 1009–1021.

  108. Williams, B.P., Read, J., and Price, J. (1991). The generation of neurons and oligodendrocytes from a common precursor cell. Neuron. 7, 685–693.

  109. Yamashita, J., Itoh, H., Hirashima, M., Ogawa, M., Nishikawa, S., Yurugi, T., Naito, M., Nakao, K., and Nishikawa, S. (2000). Flk1-positive cells derived from embryonic stem cells serve as vascular progenitors. Nature. 408, 92–96.

  110. Zandstra, P.W., Lauffenburger, D.A., and Eaves, C.J. (2000). A ligand-receptor signaling threshold model of stem cell differentiation control: a biologically conserved mechanism applicable to hematopoiesis. Blood. 96, 1215–1222.

  111. Zhu, A.J. and Watt, F.M. (1999). Beta-catenin signalling modulates proliferative potential of human epidermal keratinocytes independently of intercellular adhesion. Development. 126, 2285–2298.

  112. Zhu, A.J., Haase, I., and Watt, F.M. (1999). Signaling via beta1 integrins and mitogen-activated protein kinase determines human epidermal stem cell fate in vitro. Proc. Natl. Acad. Sci. U. S. A. 96, 6728–6733.

  113. Zulewski, H., Abraham, E.J., Gerlach, M.J., Daniel, P.B., Moritz, W., Muller, B., Vallejo, M., Thomas, M.K., and Habener, J.F. (2001). Multipotential nestin-positive stem cells isolated from adult pancreatic islets differentiate ex vivo into pancreatic endocrine, exocrine, and hepatic phenotypes. Diabetes. 50, 521–533.

Stem Cells 101

Summary: What is an Adult Stem Cell?

  • Adult stem cells can proliferate without differentiating for a long period (a characteristic referred to as long-term self-renewal), and they can give rise to mature cell types that have characteristic shapes and specialized functions.

  • Some adult stem cells have the capability to differentiate into tissues other than the ones from which they originated; this is referred to as plasticity.

  • Adult stem cells are rare. Often they are difficult to identify and their origins are not known. Current methods for characterizing adult stem cells are dependent on determining cell surface markers and observations about their differentiation patterns in test tubes and culture dishes.

  • To date, published scientific literature indicates that adult stem cells have been derived from brain, bone marrow, peripheral blood, dental pulp, spinal cord, blood vessels, skeletal muscle, epithelia of the skin and digestive system, cornea, retina, liver, and pancreas; thus, adult stem cells have been found in tissues that develop from all three embryonic germ layers.

  • Hematopoietic stem cells from bone marrow are the most studied and used for clinical applications in restoring various blood and immune components to the bone marrow via transplantation. There are at least two other populations of adult stem cells that have been identified from bone marrow and blood.

  • Several populations of adult stem cells have been identified in the brain, particularly the hippocampus. Their function is unknown. Proliferation and differentiation of brain stem cells are influenced by various growth factors.

  • There are now several reports of adult stem cells in other tissues (muscle, blood, and fat) that demonstrate plasticity. Very few published research reports on plasticity of adult stem cells have, however, included clonality studies. That is, there is limited evidence that a single adult stem cell or genetically identical line of adult stem cells demonstrates plasticity.

  • Rarely have experiments that claim plasticity demonstrated that the adult stem cells have generated mature, fully functional cells or that the cells have restored lost function in vivo.

What Do We Need to Know About Adult Stem Cells?

  • What are the sources of adult stem cells in the body? Are they "leftover" embryonic stem cells, or do they arise in some other way? And if the latter is true—which seems to be the case—exactly how do adult stem cells arise, and why do they remain in an undifferentiated state, when all the cells around them have differentiated?

  • Is it possible to manipulate adult stem cells to increase their ability to proliferate in vitro, so that adult stem cells can be used as a sufficient source of tissue for transplants?

  • How many kinds of adult stem cells exist, and in which tissues do they exist? Evidence is accumulating that, although they occur in small numbers, adult stem cells are present in many differentiated tissues.

  • What is the best evidence that adult stem cells show plasticity and generate cell types of other tissues?

  • Is it possible to manipulate adult stem cells to increase their ability to proliferate in vitro so that adult stem cells can be used as a sufficient source of tissue for transplants?

  • Is there a universal stem cell? An emerging concept is that, in adult mammals, there may be a population of "universal" stem cells. Although largely theoretical, the concept has some experimental basis. A candidate, universal adult stem cell may be one that circulates in the blood stream, can escape from the blood, and populate various adult tissues. In more than one experimental system, researchers have noted that dividing cells in adult tissues often appear near a blood vessel, such as candidate stem cells in the hippocampus, a region of the brain [75].

  • Do adult stem cells exhibit plasticity as a normal event in vivo? If so, is this true of all adult stem cells? What are the signals that regulate the proliferation and differentiation of stem cells that demonstrate plasticity?

Stem Cells 101

Pages

Subscribe to Stem Cells Portal - Stem Cells Journal Online Community RSS