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Stem Cells - Part II

Stem Cells - Part II 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?
Hematopoietic and stromal 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.

  • 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.

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?

V. 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.

VI. What are the potential uses of human stem cells and the obstacles that must be overcome before these potential uses will be realized?
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.

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.

The NIH has a wide array of new scientific programs designed to support research that uses embryonic stem cell lines.



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Copyright © 2003 Nucleus Medical Art, Inc. All Rights Reserved.
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