Stem Cells: The Basics*

What is a stem cell? Simply put, it is a primitive, undifferentiated cell that gives rise to other types of cells. Cells have a finite lifespan, and thus most cells in the body duplicate and replenish themselves. Through the isolation and targeted manipulation of cells in culture, scientists are finding ways to identify the various types of stem cells in order to find ways to use them to replace diseased, damaged, or dead cells in the body that cannot repair themselves. It’s analogous to the concept of an organ transplant, except this time scientists are transplanting stem cells, not organs.

Stem cells share the three following general characteristics:

1. The ability to differentiate into specialized cells.
2. The ability to regenerate an infinite number of times.
3. The ability to relocate and differentiate where needed.

There are three main classes of stems cells: totipotent, pluripotent, and multipotent.

Totipotent Cells: After fertilization (union of sperm and egg), the zygote created is a totipotent cell, meaning it has the genetic potential to create every cell of the body and the nourishing placenta and extra-embryonic tissues, and thus can form a human being. This one totipotent cell divides into multiple totipotent cells for up to five days (three to four cellular divisions) after fertilization.

Pluripotent Cells (aka Embryonic Stem Cells): After about five days, these totipotent cells begin to differentiate, or specialize, and form a hollow ball of cells called a blastocyst. The blastocyst has an outer layer of cells (which becomes the placenta and fetal-supporting tissues within the uterus) and a cluster of cells inside the hollow sphere called the inner cell mass (which becomes every cell of the body). This inner cell mass constitutes pluripotent cells, meaning they each have the potential to create every cell of the body but not the necessary placenta and extra-embryonic tissues, and thus cannot form a human being. Pluripotent cells can be isolated from embryos and the germ line cells of fetuses.

Multipotent Cells: Pluripotent cells soon undergo further specialization into multipotent cells (sometimes referred to as adult stem cells, multipotent adult progenitor cells, or MAPCs), which can give rise to a limited number of other particular types of cells. For example, hematopoietic cells (blood cells) in the bone marrow are multipotent and give rise to the various types of blood cells, including RBCs, WBCs, and platelets. Multipotent cells are found in both developing fetuses and fully developed human beings. There are certain limitations to using multipotent cells, however. Scientists have not identified multipotent cells for every type of mature body cell; so far, private research has isolated about 60 different types. Unlike pluripotent cells, multipotent cells are often in minute quantities and their numbers can decrease with age. Multipotent cells from a specific patient may take time to mature in culture in order to produce adequate amounts for treatment. They can and often do contain DNA damage due to aging, sunlight (radiation), toxins, and random DNA mutation during replication. Spontaneous mutations are more likely to show up in older multipotent cells than younger pluripotent cells. In addition, multipotent cells may or may not offer the same level of plasticity as pluripotent cells, although this is presently an unresolved issue. Research on the early stages of cell specialization may not be possible with multipotent cells because they are further along the specialization pathway. Thus, study of both pluripotent and multipotent stem cells is vital to fully understand cell specialization and potentially develop new treatments or even cures for diseases.

Source:  National Institutes of Health, http://www4.od.nih.gov/stemcell/fig2.gif

There are three ways thus far in which scientists can isolate human pluripotent cell lines. Other methods currently under research, including parthogenesis, have not been successful with human cells.

Inner Cell Mass Isolation from Embryonic Tissue: The inner cell mass of the blastocyst of an embryo constitutes pluripotent cells. With permission from patients, researchers obtain excess embryos from in-vitro fertility clinics to isolate these cells, which are called embryonic stem cells (ES).

Primordial Germ Line Isolation from Fetal Tissue: Pluripotent stem cells can be derived from the primitive germ line stem cells that exist from the blastocyst stage until their migration to and conversion within the developing gonads into either sperm or egg stem cells. Researchers obtain these stem cells from terminated pregnancies, where parents independently decide to end the pregnancy and give consent. These cells are called embryonic germ line stem cells (EG) and have very similar properties to ES.

Source:  National Institutes of Health, http://www4.od.nih.gov/stemcell/fig3b.gif

Somatic Cell Nuclear Transfer (aka “Therapeutic Cloning”): This process involves the use of an unfertilized egg cell. First, the nucleus of the egg is removed. Then, the nucleus of a somatic cell (body cell) is transplanted into the enucleated egg. The egg contains special factors to "reprogram" the genes of the body cell nucleus so that the result is a totipotent cell. The cell is kept in culture in a nutrient bath for a few days until cellular division creates a cluster of 120 pluripotent cells, which researchers then isolate. There are a few critical points to keep in mind. Unlike the traditional method where a sperm and egg unite to form a totipotent zygote, nuclear transplantation involves the use of an unfertilized egg to form a totipotent cell. Also, this cell is not implanted into a uterus and thus cannot develop into a human being on its own, a point that Reeve stresses in his advocacy for nuclear transplantation. This is not reproductive cloning, but a way to produce stem cells that are compatible with a person’s own body.

While scientists continue to try and isolate other adult stem cells (multipotent cells) in the body, the greatest potential seems to lie in embryonic (pluripotent) stem cells. This research will allow for the following:

• Pluripotent stem cell research will allow scientists to study factors involved in cell specialization, which is needed if stem cells can be used therapeutically. Scientists will need to know how to direct a stem cell to function specifically as a heart cell, liver cell, neuronal cell, etc. This regenerative therapy could solve the transplant supply shortage problem in hospitals.
• By studying normal cell specialization, scientists will gain insight into the specific causes of diseases, which are most often the result of abnormal cell division and/or cell specialization. Although animal testing is helpful, it cannot always reveal the exact pathology and etiology of human disease.
• Human pluripotent stem cell research could change pharmaceutical drug testing. All drugs go through extensive trials before being tested on humans or getting FDA approval. Pharmacologists could use human stem cell lines to test drugs, which could decrease animal testing and prove safer for human trials. This would reduce costs and streamline the approval process.
• Stem cells could be directed to function as heart cells to replace those damaged in a heart attack.

A recently raised issue facing researchers is whether adult stem cells (multipotent) can in fact be directed to specialize into various different cell lines like pluripotent cells can. If so, this could sidestep several ethical issues and perhaps make Reeve’s dream of walking again a reality. Also, since the multipotent cells would come from Reeve’s own body, they would not be rejected during transplantation.

Several studies thus far have led researchers to believe adult stem cells can indeed be manipulated like embryonic stem cells. NIH researchers injected adult bone marrow stem cells into areas of the heart damaged by heart attack in mice. Newly formed heart tissue occupied 68% of the damaged ventricles nine days after transplantation, suggesting that the bone marrow cells specialized into heart muscle cells. Researchers at Duke University Medical Center have shown that adult liver stem cells responded to the tissue microenvironment of the heart in mice to repair damaged heart muscle. University of Minnesota Stem Cell Institute researchers, headed by Dr. Catherine Verfaillie, transplanted adult bone marrow stem cells from rats and humans into mice and found that the cells differentiated according to their environment. For example, if they were injected into the liver, lung, or stomach, they specialized into those cell types. Also, the stem cells did not divide uncontrollably. Verfaillie and her colleagues believe that selected adult bone marrow stem cells can act as multipotent adult progenitor cells (MAPCs), meaning they are as versatile as embryonic (pluripotent) stem cells and can be manipulated to the same extent.

Editor’s Note: This material was developed based on information current in late 2002/early 2003.

*Excerpted “Saving Superman: A Look into Stem Cell Research” by Lisa M. Rubin. Copyright held by the National Center for Case Study Teaching in Science, University at Buffalo, State University of New York. Used with permission.

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