Stem Cell Biology — Where We’ve Been and Where We’re Heading

By: Dr. Greg Wall, BioFiles 2008, 3.11, 4.

BioFiles 2008, 3.11, 4.

Dr. Greg Wall, Ph.D.

Unraveling and exploring the mysteries of life have been driving forces behind scientific studies since Aristotle first attempted to understand the origins of life. Through the eyes of the microscope, cellular processes have been observed, investigated, understood, and manipulated. This quest has intensified with the discovery of embryonic and adult stem cells. In recent years the genetic modification of stems cells, and the latest discovery, the transformation of somatic cells into stem cells have emerged as primary areas of therapeutic biomedical research. Potentially, stem cells can be transformed into any of the over 200 specialized cells in the body. Their use in cell-based therapies, drug development, and new disease models is still in its infancy. The future potential in basic and applied clinical research is fueled by over 2,000 articles published yearly.

Since the 1950s, adult stem cells have been used in bone marrow transplants and to develop a variety of treatments for diseases. Bone marrow transplants are used to treat malignant diseases such as acute and chronic leukemias, Hodgkin’s disease and non-Hodgkin’s lymphoma, myelodysplasia, multiple myeloma, myelofibrosis, and renal cell carcinoma. Increasingly, success has been seen in the treatment of other diseases including aplastic anemia, sickle cell anemia, immune deficiency disorders, and autoimmune diseases such as scleroderma and multiple sclerosis. It was not until 1963 that the first qualitative description of bone marrow cell’s self-renewing activities by Ernest McCulloch and James Till, Ontario Cancer Institute, established the concept of stem cells.1 The first embryonic stem cells derived directly from the blastocyst in culture was reported by Martin Evans and Matthew Kaufman, University of Cambridge, in 1981.2 During the 1980s and 1990s, techniques for targeting and altering genetic material and growing human cells in the laboratory flourished and laid the groundwork for human stem cell research. It was observed that telomerase activity is expressed in unspecialized stem cells and progenitor cells, but suppressed in somatic cells, and specific cell surface antigens SSEA-3, SSEA-4, Tra-1-60 and Tra-1-81 can be used to identify stem cells.

The first cloning of a mammal by somatic cell nuclear transfer (SCNT) in 1997 by Ian Wilmut, Roslin Institute, demonstrated mammalian differentiated cells can be transformed to an undifferentiated state by trans-acting factors present in the oocyte. This was followed by the search for factors that could mediate similar reprogramming of somatic cells.3 The following year, James Thomson, University of Wisconsin - Madison, used trans-acting factors to reprogram isolated cells from the inner cell mass of early embryos, leading to the development of the first human stem cell lines and John Gearhart, Johns Hopkins University, derived human embryonic germ cells from primordial germ cells.4,5 Pluripotent stem cell lines were then prepared from both. Subsequent research has yielded a better understanding of the characteristics, growth, and differentiating properties of adult and embryonic stem cells. Researchers are now beginning to identify the transcription factors necessary to reprogram human somatic cells to induced pluripotent stem cells.

The reprogramming and induction of human somatic cells to stem cells that exhibit the characteristics of embryonic stem cells have been pursued by many laboratories and was reported in separate papers by Shinya Yamanaka, Kyoto University, and James Thomson, University of Wisconsin - Madison, in 2007. Their findings were based on the similarity to human embryonic stem cells in morphology, proliferation mechanisms, surface antigens, pluripotent cell-specific gene epigenetic status, and telomerase activity. Yamanaka utilized Oct3/4, Sox2, Kif4, and c-Myc transcription factors to reprogram human dermal fibroblast cells. In this method, c-Myc and Klf4 may be involved in modifying chromatin structures so that Oct3/4 and Sox2 bind to their targets. Thomson transduced IMR90 fibroblast and postnatal fibroblast cells with a combination of Oct4, Sox2, Lin28, and NANOG. Lin28 and NANOG have been shown to improve cloning efficiency and recovery. The induced pluripotent human stem cells by both methods maintained their ability to differentiate into all three germ layers in vitro.

One potential limitation of the Yamanaka method using the c-Myc factor would be mutation through viral integration. The altered or forced expression of c-Myc may result in unwanted differentiation of the induced pluripotent stem cells. By using different transcription factors to reprogram and generate cells having the same characteristics as stem cells, the viability of this technology has been validated as a method to induce somatic cells. The induction process and how to harness it is now under further investigation.

Paralleling this achievement, research groups have continued to make progress in developing methods to improve the efficiency of human therapeutic cloning via SCNT. Advances have been made in the preparation of recipient cytoplasts, preparation and transfer of donor DNA, and parthenogenic activation of embryonic development. Recently, Andrew French, Stemagen Corporation, has been able to clone blastocysts from somatic cells.8 The ability to prepare nuclear transfer stem cells by this method is promising to regenerative medicine and cell-based drug discovery.

The preparation of human induced pluripontent stem cells is a milestone in stem cell biotechnology as is its impact on medical applications. This opens up the possibility of using them as well as embryonic stems cells in treating medical conditions such as cancer and birth defects, along with generating tissue for arthritis, burns, diabetes, heart disease, strokes, spinal cord injury, and disabilities like Alzheimer’s and Parkinson’s disease. Currently hematopoietic stem cells are the only stem cells being used in the treatment. Human induced pluripotent stem cells may have a role in drug development for efficacy or toxicity screening; thus, eliminating the need for animal testing and shortening the time to commercialization. They open the window for personalized medical treatment with cell-based therapies based on stem cells that contain the genetic makeup or genetically engineered DNA of the patient.

The study of embryonic stem cells will continue to further our understanding of how they transform. Both private and government funding of embryonic stem cell research will be critical to reach this goal to provide a platform for the future. Human induced stems cells eliminate the need to use human embryos; thus, minimizing or even eliminating cultural, political, religious, and ethical concerns. The commercial and social impact to be gained by stem cell research coming to fruition is immeasurable. The ability to use stem cells instead of scalpels will affect how we practice medicine and approach personalized healthcare. As our understanding of genomics and proteomics has enriched our appreciation of the complexities of life, our exploration of stem cells will solve even more of its mysteries.

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  1. Becker, A.J., et al., Cytological demonstration of the clonal nature of spleen colonies derived from transplanted mouse marrow cells. Nature, 197, 452-454 (1963).
  2. Evans, M.J., and Kaufman, M.H., Establishment in culture of pluripotential cells from mouse embryos. Nature, 292, 154-156 (1981).
  3. Wilmut, I., et al., Viable offspring derived from fetal and adult mammalian cells. Nature, 385, 810-813 (1997).
  4. Thompson, J.A., et al., Embryonic Stem Cell Lines Derived from Human Blastocysts. Science, 282, 1145-1147 (1998).
  5. Gearhart, J., et al., Derivation of pluripotent stem cells from cultured human primordial germ cells. P.N.A.S., 95, 13726-13731 (1998).
  6. Yamanaka, S., et al., Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell, 131, 861-872 (2007)
  7. Thomson, J.A., et al., Induced Pluripotent Stem Cell Lines Derived from Human Somatic Cells. Science, 318, 1917-1920 (2007).
  8. French, A.J., et al., Development of Human cloned Blastocysts Following Somatic Cell Nuclear Transfer (SCNT) with Adult Fibroblast. Stem Cells published online Jan 17, 2008,
  9. Dr. Greg Wall, Ph.D., BioChemSultants, LLC

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