Research on stem cells

C. Ward Kischer, Ph.D.

Origin of the term "stem cell"

The phrase "stem cell" or "stem cells" actually came from histologists. It has been in the histology texts for a long, long time. But, they have been listed as "regenerative" or "reparative" cells. Virtually every tissue in the human body has its stem cells. These cells are present to either replace lost cells, or damaged tissue with substitute cells or tissue, such as scar tissue. These cells are partially differentiated, but not terminally differentiated. What characterizes these cells when called upon to divide is their ability for self renewal. When a stem cell divides one daughter cell becomes differentiated while the other daughter cell remains a stem cell to divide again. In some tissues they are easily identified; but, in other tissues, they are very difficult to identify [Kischer, et al., 1982. Hypertrophic scars and keloids: a review and new concept concerning their origin. Scanning Electron Microscopy, iv: 1699-1713; Kischer, et al., 1989. Increased fibronectin production by cell lines from hypertrophic scar and keloid. Connective Tissue Research, 23:279-288; Kischer, C.W. and J. Pindur. 1990. Effects of platelet derived growth factor (PDGF) on fibronectin (FN) production by human skin and scar fibroblasts. Cytotechnology, 3:231-238.]

Throughout the length of the gut there are many different types of cells, virtually all of which are replaced. The gut probably has the highest incidence of replacement of any tissue of the human body. Some of the cell types are replaced every 4 to 5 days, whereas others are replaced from 3 to 6 weeks. All of the replacement is accomplished by stem cells.

Perhaps the best known details of histologic stem cells comes from the work on the hematopoietic stem cells of blood and bone marrow. This data has been largely derived from the work of Fowler, et al. and Siminovitch, et al. [Cited by: Histology: Cell and tissue biology. 1983. 5th edition. Ed., Leon Weiss, pp: 495-497].

Stem cells from human embryos

Some years ago, the exact source may be unknown, some enterprising molecular biologist, or, maybe a developmental biologist, commandeered the term "stem cell" and applied it to the cells of an early embryo which make up an "inner cell mass" (ICM). This would be a time post-fertilization before the early embryo has formed its first body axis. This would correspond to a time prior to 14 days post - fertilization. The idea proposed was that these "inner cell mass" cells would not be differentiated and would, therefore, be better than histologic "stem cells", in that they would be "totipotent" undifferentiated cells. The further prediction has been that because this is believed to be the case the "inner cell mass" cells should be able to be coaxed or prodded chemically to differentiate into any one or all of the hundreds of different cell types in the human body. The conclusion of this scheme is that these cell types will be grown in culture as tissues and would then be used therapeutically to replace lost, damaged or diseased differentiated tissues in the adult human.

There are several problems with this proposition, not the least of which is that it is not known if all the cells of the "inner cell mass" of the human embryo are, indeed, the same; that is, are, indeed, all totipotent. It is clear that the term "stem cell" is being used to define two different "potential" biologic states. But, few, apparently, are concerned with this. Thus, many researchers are lobbying for federal support for research on the human embryonic "stem cells" of the "inner cell mass".

The term "Embryonic stem cells" has now found its way into at least one Human Embryology textbook [Larsen, William J. 2001. Human Embryology. 3rd edition. p. 505. Churchill - Livingstone, New York.]. It appears in the Glossary, but not in the text proper. The definition is given as follows:

Arise from the inner cell mass during in vitro culture of blastocysts removed from a fertilized genital tract; totipotent; produce injection chimeras when introduced into a normal blastocyst.

This definition describes what is known from studies in mice. Equivalent studies in the human have not yet been reported.

Current status of stem cell research from human embryo sources

Other problems are predictable in projected therapeutic use of human embryonic stem cells (hesc). For example, tissues (or cells) differentiated from a non-autologous source, if injected for treatment, would eventually be rejected. Therefore, immunosuppressive therapy would be indicated.

Further, in some studies of mice, it has been shown that injection of hesc form tumors in the recipient. [Transcripts, Third Meeting, April 25, 2002, President's Council on Bioethics]. Any tissues developed for patients from hesc must not develop tumors and must have the innate ability to respond to the normal signals that tell tissues to grow, stop growing or heal.

In sum, the reports of producing differentiated cell types from the 60 or so cell lines which are on hand, world-wide, are not encouraging. John Gearhart, stem cell biologist from Johns Hopkins University, testified before President Bush's Council on Bioethics [Transcripts, Third Meeting, April 25, 2002] that the results on existing cell lines has, so far, been unproductive.

A recent report has come from Advanced Cell Technology, Worcester, Massachusetts, of human therapeutic cloning which, reportedly, "produced three somatic cell - derived embryos up to the six cell stage." [ Cibelli et al. 2001. Somatic Cell Nuclear Transfer in Humans: Pronuclear and Early Embryonic Development. e-biomed: J. Regenerative Medicine, 2:25-31]. However, the data appear faulty. In fact,

John Gearhart, stem cell biologist, said the study should be considered a failure and that it should not have been published. He resigned as an editorial advisor of the online publication because of the questionable quality of the report.

This same company, headed by Dr. Michael West, has published another report [Cibelli et al. 2002. Parthenogenetic Stem Cells in Nonhuman Primates. Science, 295:819] claiming the derivation of at least four differentiated cell lines from parthenotes derived from monkeys. They claim that such lines can obviate the necessity for using hesc. But, what of the fact that the cells from these cell lines have only maternal chromosomes and are likely to contain lethal genes? There is no mention of this in the report.

The company of Advanced Cell Technology, again, has announced the results of a new study involving nuclear transplantation (cloning) online in the July issue of the journal Nature Biotechnology, in collaboration with Harvard Medical School. Working with cloned bovine cells they claim to show that their would be no rejection of the cell lines produced because of "foreign DNA from a donated egg". Senior author Robert Lanza states: "This study furnishes the first scientific evidence that cloned tissues can be transplanted back into animals without being destroyed by the body's immune system."

Stem cell research from human adult tissue sources

K. Hamano reported at the American Heart Association's 2001 meeting in Anaheim, California that his team from Yamaguchi University School of Medicine in Ube, Japan, obtained stem cells from bone marrow of several patients with heart disease. They injected the stem cells back into the hearts of the patients and demonstrated improvement in blood flow in 3 of 5 patients.

Lorraine Iacovitti from Jefferson Medical College in Philadelphia, reported on November 11, 2001 at the meeting of the Society of Neuroscience in San Diego that adult human bone marrow cells can be converted into brain cells (neurons) and subclasses of neurons. This team is working on converting these cells into dopamine producing neurons. If so, the benefits for Parkinson's patients can be enormous.

Piero Anversa from the New York Medical College in Valhalla, New York claims to have discovered the presence of cardiac stem cells in the human heart. His group performed autopsies on eight males who had received heart transplants from females. Cells containing Y-chromosomes (male cells) were found proliferating within the female hearts. These cells are theorized to have migrated from remnants of the original male heart or from the bone marrow of the recipient. They were found to have differentiated into muscle cells and blood vessels.

Perhaps the most exciting new studies come from Catherine Verfaille from the University of Minnesota who claims she and her research team have isolated special stem cells from the bone marrow of adults, which have the potential to differentiate into many different types of body tissues [2002. Origin of endothelial progenitors in human postnatal bone marrow. J. Clin. Invest. 109:337-346]. She calls these cells "multipotent adult progenitor cells" (MAPCs). She has carried out experiments in which she placed single MAPCs from humans and mice into very early mouse embryos. Analysis of the mice born after the experiment showed that a single MAPC can contribute to all the body's tissues.

A Duke University research team, has reported that adult stem cells from fat can be reprogrammed into bone and cartilage cells. They reported their findings at the February 10th, 2002, annual meeting of the Orthopedic Research Society, and recently in published form [Yuan - Di, C. et al. 2002. Extracellular matrix mineralization and osteoblast gene expression by human adipose tissue - derived stromal cells. Tissue Engineering. 7:729-741].

Also at a February meeting of the American Association for the Advancement of Science, Jack Parent, professor of Neurology at the University of Michigan Medical School, reported studies in rats in which adult neural stem cells were found to migrate toward brain areas damaged by prolonged epileptic seizures and strokes. Five weeks after the stroke some had even developed into neurons, and showed evidence of differentiating into neurons specific to the areas.

Conclusions

  1. The correct terminology has yet to be established for human embryonic "stem cell" research.

  2. The publications from Advanced Cell Technology, Worcester, Massachusetts must be thoroughly evaluated and repeated by others for authenticity.

  3. The short and long term effects of therapeutic cloning must be thoroughly evaluated in animal studies before any thought is given towards human embryo therapeutic cloning.

  4. Parthenogenesis should not be an option for producing cell lines for cellular therapies if for no other reason than the likelihood of the cells containing lethal genes.

  5. Every effort should be made to investigate the possibilities of using adult "stem cells" for prospective therapies in diseased human beings.


Ward Kischer is an emeritus professor of Anatomy (specialty in Human Embryology) at the University of Arizona, College of Medicine, Tucson, Arizona. Comments and questions will be most appreciated at wkisch@netzero.net.

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