May 2007 | Back to Table of Contents

Clinical and Health Affairs

A Primer on Stem Cell Research

By Meri Firpo, Ph.D., and Nobuaki K. Kikyo, M.D., Ph.D.

Abstract
Stem cell research holds promise for new treatments for diseases such as Parkinson’s and injuries such as those to the spinal cord. Yet stem cell research remains steeped in controversy. This article defines key terms and outlines some of the basic concepts related to stem cell research in order to clarify concepts and correct misconceptions. It also briefly discusses what scientists, particularly those at the University of Minnesota, are learning about adult and embryonic stem cells and their potential for research and treatment. 

From scientific, political, and ethical perspectives, news regarding stem cell research attracts attention. Because of this, the public and even the medical community is often exposed to oversimplified, and at times inaccurate, information about the state of stem cell research and the science behind it.

The study of stem cells began more than 40 years ago, as researchers saw the potential for using stem cells in bone marrow to treat people with various cancers and blood disorders. In 1968, the world’s first successful human bone marrow transplant was performed at the University of Minnesota to treat a 4-month-old boy with immune deficiency syndrome.¹ Since then, new discoveries have been made and tested almost weekly. Because tissue regeneration factors into so many diseases, the promise of stem cells for therapeutic purposes seems potentially limitless.

As researchers at a public research institution, we feel it is part of our mission to educate the larger community about stem cells so that there can be meaningful dialog about this relatively new and highly promising area of research. The aim of this article is to define some of the common terms to help foster a productive discussion about this field.

What Is a Stem Cell?
Stem cells, broadly defined, are the cells that can give rise to and maintain all types of tissues and cells. Stem cells are found in most tissues and have been investigated systematically in bone marrow, blood, brain and nerves, liver, skin and muscle, as well as in the placenta and umbilical cord blood. Because they function as “parent” cells, stem cells are useful for studying development, and they offer great potential in terms of future treatment of disease. A combination of two characteristics sets stem cells apart from other types of cells (functional postmitotic cells and their precursors): their ability to self-renew and their ability to differentiate into different types of cells during proliferation.

In vivo, these versatile cells repair and, in some cases, replace damaged tissue. The balance between self-renewal and differentiation during proliferation regulates regeneration of tissue as well as functional, long-term engraftment after transplantation. Scientists are working to understand the full potential and capacity to differentiate of both adult stem cells (including those found in individual organs, those from umbilical cord blood, and those from bone marrow) and embryonic stem cells.

Adult Stem Cells
Adult stem cells can give rise to different cell types within a tissue or organ. For example, adult neural stem cells found in the brain give rise to neurons, astrocytes, and oligodendrocytes. Scientists currently believe adult stem cells are found in nearly all tissues and organs; they are cells that have already differentiated and can be sourced from fetal tissue, placentas, cord blood, bone marrow, and even organs. These adult stem cells are generally considered to be monopotent or oligopotent because their differentiation potential is restricted to the cells of the organ where they reside. The most frequently used adult stem cell in terms of clinical treatment is the blood-forming, or hematopoietic, stem cell. Found in the bone marrow, these cells have been used for more than 30 years to cure a wide spectrum of diseases, mainly leukemias and lymphomas, through bone marrow transplantation.

Adult stem cells are also found in the umbilical cord blood that is harvested after a baby is born. These cells are also used in transplantation for patients with various blood disorders. Adult stem cells isolated from other tissues and organs can be used for treatment as well. For example, keratinocyte stem cells have been used to provide allogeneic transplantation for catastrophic skin loss from burns.² Stem cells from other tissues are being investigated for similar transplantation therapies. There is debate among the scientific community about whether some adult stem cells are, in fact, multipotent and thus have the ability to differentiate into cell types other than those of the organ from which they originate. University of Minnesota research has shown that when cultured in very specific conditions, some adult stem cells can differentiate into representative cell types of each of the ³ embryonic germ layers—endoderm, mesoderm, and ectoderm.3

Researchers at the university are also studying transplantation of hematopoietic stem cells for the repair of heart muscle tissue. Early preclinical and clinical studies have suggested that infusions of some types of adult stem cells may help improve function in cardiac tissue.⁴ What remains to be seen and will require further study is the mechanism by which transplantation of these cells improves that function.

In terms of figuring out applications for adult stem cells in treating other diseases, more research must be done to investigate stem cell plasticity and the therapeutic applications resulting from transdifferentiation and fusion-mediated correction of tissue damage or genetic defects after transplantation.

Embryonic Stem Cells
Embryonic stem cells are pluripotent; therefore, they can give rise to all cell types in the body, suggesting that they may be more versatile than adult stem cells. Embryonic stem cells are derived from preimplantation embryos 5 to 6 days after fertilization; and, unlike most adult stem cells, they can be expanded for long periods of time in culture without differentiating. Embryonic stem cells have been isolated from mice, humans, and nonhuman primates. Because of their unique combination of properties, embryonic stem cells provide potential novel sources of cells for pharmaceutical testing and transplantation, as well as an in vitro model of human development.

They also incite more controversy than adult stem cells. Federal funding for this research is currently limited to embryonic stem cell lines created before August 9, 2001. The law does not prohibit developing additional cell lines; they just must be developed using other funding sources. University of Minnesota policy is that state funding will not be used for embryonic stem cell lines that are ineligible for federal funding. Thus, any development of new lines here requires the support of private donors.

Embryonic stem cell lines have been derived from excess fertilized eggs that come from in vitro fertilization clinics. Couples undergoing fertility treatments who may end up with excess embryos have the option of donating them for scientific research. These embryos can be cultured to the blastocyst stage, which takes place just prior to implantation if the embryo were introduced into a uterus. For the formation of an embryonic stem cell line, cells are removed from the blastocyst, which destroys the embryo in the process. Under the appropriate conditions, the embryonic stem cells can expand without differentiation or can differentiate into any cell type in the body.

Self-renewal is typically supported by the co-culture of embryonic stem cells with mitotically inactivated fibroblast “feeder” cells. Differentiation can be achieved after cell expansion by removing the embryonic stem cells from the conditions that promote self-renewal and allow further proliferation with spontaneous or directed differentiation. These cell lines can then be used to study normal human development in vitro or to differentiate cells for transplantation therapies.

Researchers at the University of Minnesota are using embryonic stem cells to prepare many cell types for transplantation, including insulin-producing, neural, and blood cells. They also are looking at using embryonic stem cells for creating disease models in order to better understand the evolution of disease. Embryos that have been discarded after preimplantation genetic diagnosis because of abnormal karyotype can be used as an in vitro model of abnormal development and, thus, the development of the resulting disease.

Although there are currently no clinical trials involving embryonic stem cells, animal studies have shown promise for treatment of Parkinson’s disease, diabetes, and spinal cord injury.

Therapeutic Cloning or Somatic Cell Nuclear Transfer
Using embryonic stem cells, researchers now have the capability of producing tissues that are genetically identical to one another. A process called somatic cell nuclear transfer (SCNT), or more commonly, cloning, involves removing the nucleus of an unfertilized oocyte and replacing it with the nucleus of a differentiated cell such as one from the skin or blood. The oocyte containing the adult cell nucleus is then chemically or electrically stimulated to divide and begin a process of development similar to that of an early embryo. The embryo produced by SCNT can then be cultured to the blastocyst stage and used to make an embryonic stem cell line genetically identical to the original donor of the nucleus. The resulting line can then be differentiated into any cell type.

Reproductive cloning in animals has been performed using embryo cells for donor nuclei for many years, starting with frogs in 1952.⁵ The first animal cloned using an adult cell nucleus was Dolly the sheep in 1998, which brought increased attention to the use of SCNT technology for developing mammalian embryonic stem cells, and reproductive cloning.⁶ SCNT is distinct from reproductive cloning because there is no implantation, and no animal is ever created. SCNT for the production of matched cells for transplantation has proved difficult in a human model. If it works, however, the promise of self-repair comes closer to reality.

The process of creating embryonic stem cell lines by therapeutic cloning is a long one, and this approach may be most effective if it is used to create many lines from nuclear donors who are a good immune match for many individuals. In the future, researchers may be able to use this technology to create a bank of cell lines that could make cell treatments available more quickly to the people who need them.

In the future, physicians could use this process to create cells that are an exact genetic match to the patients who need them for therapeutic purposes, thus reducing or eliminating the need for immunosuppression. Scientists at private universities such as Harvard and in private companies are working to achieve such results using SCNT.

Additionally, SCNT could be used to study the development of various diseases. Scientists would use donor nuclei from diseased individuals to study the development of the genetically identical tissues. This would be particularly valuable for studying conditions such as Down syndrome that occur during development in utero because the differentiation would be accessible in culture. It would also be useful for studying diseases such as diabetes; there are no genetic tests that can predict whether an embryo is predisposed before implantation.

Basic Research on Reprogramming
One objective of SCNT research is to obtain a more clear understanding of the process of reprogramming the adult cell nucleus to function as an embryonic nucleus. Researchers have determined that the process of reprogramming an adult nucleus to function as a nucleus from a fertilized egg takes place during the epigenetic changes to the DNA of the nucleus. Thus, the DNA content of the cell is the same as that of the mature nuclear donor cells, but epigenetic modifications to the DNA or to the chromosomal structure alter the function of the genes to the embryonic state. These changes are associated with the transfer of proteins from the cytoplasm of the egg to the donor nucleus. The patterns of DNA chemical modifications, including the presence of methylation, acetylation, and phosphorylation of the DNA as well as the extension of the telomeres and the association with structural proteins of the chromosome are altered. Some or all of these changes may be responsible for reprogramming.

Some regulatory proteins implicated in reprogramming have already been identified in animals and are being investigated in human cells.⁷ A better understanding of reprogramming may give us improved therapies for a wide range of disorders including imprinting disorders, such as those that cause autism, and methods to regulate the expansion of adult stem cells and transdifferentiate them into other cell types for organ regeneration.

Conclusion
The promise of stem cell research, especially embryonic stem cell research, is still being discovered. We do not yet know which diseases will respond best to adult or embryonic stem cell treatments. And it will be years before these treatments make it into clinical practice. One thing is clear: While researchers, politicians, and the public debate the issue, patients are clamoring for the new treatment options stem cell research offers. MM

Meri Firpo is an assistant professor of medicine and Nobuaki Kikyo is an assistant professor of medicine. Both are members of the University of Minnesota’s Stem Cell Institute.

References
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