Stem Cell Research at Joslin Diabetes Center
Stem cells hold tremendous promise for treating a host of diseases, including diabetes. The viability of islet cell transplantation as a treatment for diabetes is severely limited by the lack of available islet cells, and scientists hope that stem cells may someday provide a virtually unlimited source for insulin-producing cells. They may also be useful for developing novel methods to achieve the immunological tolerance that will be required to keep new islets from being rejected, whether they were provided through transplantation or derived from stem cells. Certain types of stem cells appear to be able to repair damaged tissues, including blood vessels, throughout the body, so scientists believe that they might also be used to prevent some of the devastating medical complications of diabetes.
Joslin’s Commitment to Stem Cell ResearchJoslin Diabetes Center, a global leader in diabetes research and care, is fully committed to moving stem cell research forward by bringing together top researchers in the field. These researchers work together across several of Joslin’s research sections, including the Sections on Developmental and Stem Cell Biology, Islet Transplantation and Cell Biology, Immunology and Immunogenetics, Cellular and Molecular Physiology, and Vascular Cell Biology.
Joslin is affiliated with the Harvard Stem Cell Institute (HSCI), established in April 2004. The HSCI was founded to create an interactive community among stem cell scientists working at the many institutes affiliated with Harvard, and to provide resources and mechanisms for collaborations that will bring together their diverse expertise. A major purpose of the HSCI is to fill the funding gap left by the Bush administration’s tight restrictions of federal funding for human embryonic stem cell research. HSCI researchers have already produced a number of human embryonic stem cell lines, which they are making widely available to medical researchers, in order to foster this extremely promising area of research. Douglas Melton, Ph.D., HSCI’s Co-Director and a leading proponent of stem cell research, is an Adjunct Investigator at Joslin and a member of Joslin’s Board of Overseers. T. Keith Blackwell, M.D., Ph.D., Head of the Section on Developmental and Stem Cell Biology at Joslin, is co-organizer of the HSCI laboratory research presentation conferences; Gordon C. Weir, M.D., Head of the Section on Islet Transplantation and Cell Biology who holds the Diabetes Research and Wellness Foundation Chair at Joslin, heads the HSCI diabetes program, and Susan Bonner-Weir, Ph.D., senior investigator in the Section on Islet Transplantation and Cell Biology, heads the HSCI membership committee.
Stem Cells and DiabetesThere are two basic types of stem cells: those that can multiply to make more copies of themselves and give rise to any type of cell in the body, and those that can multiply to make more copies of themselves but are capable of yielding only a subset of cell types. Embryonic stem cells, which are derived from immature cells of the embryo, are examples of stem cells that can give rise to any type of cell in the body. Umbilical cord blood stem cells, or adult stem cells such as bone marrow or brain stem cells, that exist in tissues after birth, are examples of stem cells that may give rise to a more limited number of cell types.
Scientists hope that stem cells may someday provide a virtually unlimited supply of healthy insulin-producing cells to transplant into people with type 1 diabetes, freeing them from the need for insulin injections. Islet transplantation (transplanting pancreatic tissue that contains insulin-producing beta cells) has shown tremendous potential, but its widespread clinical use is hampered by the very limited supply of donor tissue and the need for powerful immunosuppressive drugs. Researchers hope that stem cells might someday be grown in quantity, coaxed into differentiating to become insulin-producing cells, and transplanted into large numbers of people with type 1 diabetes.
Yet, whether transplanted islets are derived from stem cells or donor pancreatic tissue, it is likely that therapeutic interventions will be needed to prevent rejection of the transplanted cells. Here again, stem cells may have important therapeutic applications as, once the overactive immune system has been destroyed or tamed, transplantation of blood-forming stem cells may result in a new immune system that will enable patients with diabetes to better tolerate and maintain islet transplants.
Scientists also believe that stem cells may someday help to prevent the devastating complications of diabetes, which include heart disease, stroke, peripheral vascular disease, diabetic retinopathy, kidney disease, nerve damage and birth defects. Many of these complications involve damage to large or small blood vessels. Stem cells show promise repairing blood vessels, so researchers hope that they might be able to undo some of the long-term damage that results from diabetes.
Key Questions in Stem Cell ResearchJoslin researchers are investigating:
- Could embryonic or adult stem cells be cultivated and manipulated in such a way that they differentiate into insulin-producing cells? What regulatory genes must be turned on or off to make this happen and how can this cellular programming be put into place?
- Could transplanting blood-forming stem cells be used in methods to achieve immunological tolerance and so help enable people with diabetes to better tolerate islet transplants?
- Could new methods that incorporate blood-forming stem cell transplants be useful for halting the autoimmune process that leads to type 1 diabetes?
- Could blood-forming stem cells or other stem cells be used to repair tissues damaged by diabetes, such as blood vessels? By what mechanism do blood-forming stem cells regenerate tissue?
- How do diabetes and hyperglycemia block the differentiation of stem cells in tissues damaged by diabetic complications?
Stem Cells, Islet Transplantation and Beta Cell RegenerationFrom many different angles, Joslin researchers are tackling the complex task of how to coax stem cells into becoming insulin-producing cells for transplantation. T. Keith Blackwell, M.D., Ph.D., Head of the Section on Developmental and Stem Cell Biology at Joslin, has been using a simple model organism—the microscopic nematode (worm) Caenorhabditis elegans—to study the regulation of genes that are important for the development of oocytes (egg cells) and the early embryo. By studying how these developmental genes are regulated, Dr. Blackwell and colleagues hope to discover exactly how these cells differentiate into various types of cells. Based on previous research, they believe that studying these gene regulatory mechanisms will provide knowledge that may make it possible eventually to reprogram human stem cells to develop into different types of cells—including insulin-producing cells.
Gordon C. Weir, M.D., Head of the Section on Islet Transplantation and Cell Biology, who holds the Diabetes Research and Wellness Foundation Chair at Joslin, along with the section’s Senior Investigator, Susan Bonner-Weir, Ph.D., have been working with embryonic stem cells and adult precursor cells that have the capacity to become insulin-secreting cells. Much of Dr. Weir’s research focuses on studying the genetic make-up and functioning of pancreatic beta cells in the body, which could provide a blueprint for helping stem cells differentiate into insulin-producing cells.
Dr. Bonner-Weir and colleagues have shown that new islets can be formed from adult precursor cells called duct cells that have been isolated from the human pancreas. These findings offer hope that such duct cells might one day be used to provide islets for transplantation, obviating the need for immunosuppressive drugs if the transplanted islets could be derived from the patient’s own body.
Rohit N. Kulkarni, M.D., Ph.D., Investigator in the Section on Cellular and Molecular Physiology, and colleagues including C. Ronald Kahn, M.D., Vice Chairman of the Board of Trustees, Senior Investigator and Head of the Section on Obesity and Hormone Action and the Mary K. Iacocca Professor of Medicine at Harvard Medical School, are exploring the possible presence of “beta-cell stem cells” within adult islets, which are different from duct cells or traditional stem cells. Based on evidence that adult beta cells can replicate in response to insulin resistance, Dr. Kulkarni hypothesizes that these beta-cell stem cells may be able to respond to insulin resistant states or other stimuli by replicating and thus increase the beta cell mass and insulin secretion. Several approaches, including methods of lineage trace analysis, transplantation, and parabiosis experiments are being used to identify the existence of such specialized cells. If researchers can find them and discover how they work, it may one day be possible to use these cells in the earliest stages of diabetes to prevent or delay the onset of the full-blown disease.
Amy J. Wagers, Ph.D., Principal Investigator in the Section on Developmental and Stem Cell Biology, is studying the migration and function of blood-forming stem cells, which already are being used to treat such diseases as leukemia, lymphoma and immune deficiency.
Blood cell transplantation may someday help people with diabetes better tolerate islet transplants without the need for prolonged use of powerful immunosuppressive drugs, although transient immunosuppression would still be necessary to achieve engraftment of the blood-forming stem cells. In addition, transplantation of blood-forming stem cells may prove useful in strategies to halt the autoimmune process that causes type 1 diabetes.
Dr. Wagers is trying to identify and characterize the molecules that control the migration and function of these stem cells, which could allow for more effective blood cell transplantation.
The laboratory of Mary R. Loeken, Ph.D., Investigator in the Section on Developmental and Stem Cell Biology, focuses on the underlying causes of birth defects in diabetic pregnancy. Dr. Loeken and her colleagues have found that birth defects result from failure to induce specific genes needed to prevent cell death and induce differentiation at the very earliest stages of embryonic development. Her laboratory has shown that pathways activated by excess glucose metabolism are responsible for the effects of diabetes on embryo gene expression. The changes in gene expression that can be observed in mouse embryos of diabetic mothers can be replicated in mouse embryonic stem cells. Embryonic stem cells can be used to study the precise biochemical and molecular mechanisms by which high glucose and oxidative stress prevent the activation of embryonic genes, using methods that can not be performed with mouse embryos. There may be similar genes that prevent cell death and activate differentiation of progenitor c ells in the eye, kidney, nerves and blood vessels. Excess glucose metabolism may impair expression of these genes and contribute to the progression of diabetic complications affecting these tissues. Therefore, study of glucose-induced molecular processes in embryonic stem cells may help to explain the pathogenesis of diabetic complications in general, and lead to improved treatments. Dr. Loeken's laboratory is also investigating more efficient methods of isolating new embryonic stem cells from mouse embryos.