STEM CELLS

EDITORIAL

                                     STEM CELLS             

BY

M. Adel Shalaby

      Stem cells are cells in the body that haven't "become" anything. They are "undifferentiated," and their purpose is to multiply and eventually "differentiate" into one type of cell or another. They exist in all tissues, and are especially common in tissues that have to replace dead cells often (bone marrow, intestines). This is how your body replaces cells that die, and it is also how tissues are formed in the first place when a baby is first forming in the uterus.

     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.

     There are three main sources for obtaining stem cells - adult cells, cord cells, and embryonic cells. Adult stem cells can be extracted either from bone marrow or from the peripheral system. Stem cells taken from the umbilical cord are a second very rich source of stem cells. Embryonic stem cells are extracted directly from an embryo before the embryo's cells begin to differentiate. At this stage the embryo is referred to as a "blastocyst." There are about 100 cells in a blastocyst, a very large percentage of which are stem cells, which can be kept alive indefinitely, grown in cultures, where the stem cells continue to double in number every 2-3 days. A replicating set of stem cells from a single blastocyst is called a "stem cell line" because the genetic material all comes from the same fertilized human egg that started it. Compared to adult cells and embryonic cells, the umbilical cord is by far the richest source of stem cells, and cells can be stored up in advance so they are available when needed.

     Human embryonic and adult stem cells each have advantages and disadvantages regarding potential use for cell-based regenerative therapies. One major difference between adult and embryonic stem cells is their different abilities in the number and type of differentiated cell types they can become. Embryonic stem cells can become all cell types of the body because they are pluripotent. Adult stem cells are thought to be limited to differentiating into different cell types of their tissue of origin. Embryonic stem cells can be grown relatively easily in culture. Adult stem cells are rare in mature tissues, so isolating these cells from an adult tissue is challenging, and methods to expand 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.

     Adult stem cells, and tissues derived from them, are currently believed less likely to initiate rejection after transplantation. This is because a patient's own cells could be expanded in culture, coaxed into assuming a specific cell type (differentiation), and then reintroduced into the patient. The use of adult stem cells and tissues derived from the patient's own adult stem cells would mean that the cells are less likely to be rejected by the immune system. This represents a significant advantage, as immune rejection can be circumvented only by continuous administration of immunosuppressive drugs, and the drugs themselves may cause deleterious side effects.

      Induced pluripotent stem cells (iPSCs) are adult cells that have been genetically reprogrammed to an embryonic stem cell–like state by being forced to express genes and factors important for maintaining the defining properties of embryonic stem cells. Although these cells meet the defining criteria for pluripotent stem cells, it is not known if iPSCs and embryonic stem cells differ in clinically significant ways. 

       There are many ways in which human stem cells can be used in research and the clinic. Studies of human embryonic stem cells will 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 the differentiated cells that form the tissues and organs. 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 more complete understanding of the genetic and molecular controls of these processes may yield information about how such diseases arise and suggest new strategies for therapy. Predictably controlling cell proliferation and differentiation requires additional basic research on the molecular and genetic signals that regulate cell division and specialization.

       Human stem cells are currently being used to test new drugs. New medications are tested for safety on differentiated cells generated from human pluripotent cell lines. Other kinds of cell lines have a long history of being used in this way. Cancer cell lines, for example, are used to screen potential anti-tumor drugs. The availability of pluripotent stem cells would allow drug testing in a wider range of cell types.

      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. 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 macular degeneration, spinal cord injury, stroke, burns, heart disease, diabetes, osteoarthritis, and rheumatoid arthritis.

     It may become possible to generate healthy heart muscle cells in the laboratory and then transplant those cells into patients with chronic heart disease. Whether these cells can generate heart muscle cells or stimulate the growth of new blood vessels that repopulate the heart tissue, or help via some other mechanism is actively under investigation.

      Cardiovascular disease can deprive heart tissue of oxygen, thereby killing cardiac muscle cells (cardiomyocytes). This loss triggers a cascade of detrimental events, including formation of scar tissue, an overload of blood flow and pressure capacity, the overstretching of viable cardiac cells attempting to sustain cardiac output, leading to heart failure, and eventual death. Restoring damaged heart muscle tissue, through repair or regeneration, is therefore a potentially new strategy to treat heart failure.

      The use of embryonic and adult-derived stem cells for cardiac repair is an active area of research. A number of stem cell types, including embryonic stem (ES) cells, cardiac stem cells that naturally reside within the heart, myoblasts (muscle stem cells), adult bone marrow-derived cells including mesenchymal cells (bone marrow-derived cells that give rise to tissues such as muscle, bone, tendons, ligaments, and adipose tissue), endothelial progenitor cells (cells that give rise to the endothelium, the interior lining of blood vessels), and umbilical cord blood cells, have been investigated as possible sources for regenerating damaged heart tissue. A few small studies have also been carried out in humans, usually in patients who are undergoing open-heart surgery. Several of these have demonstrated that stem cells that are injected into the circulation or directly into the injured heart tissue appear to improve cardiac function and/or induce the formation of new capillaries. The stem cell populations that have been tested in these experiments vary widely, as do the conditions of their purification and application. Although much more research is needed to assess the safety and improve the efficacy of this approach, these preliminary clinical experiments show how stem cells may one day be used to repair damaged heart tissue, thereby reducing the burden of cardiovascular disease.

      In people who suffer from type 1 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 persons with diabetes.

     To be useful for transplant purposes, stem cells must be reproducibly made to:

- Proliferate extensively and generate sufficient quantities of cells for making 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 as the problem of immune rejection.

Stem cells offer exciting promise for future therapies, but significant technical works and intensive research are still needed.

Associate Editor 

Prof. Dr. Mohamed Adel Shalaby