MARCH 2003 - In a finding that may open a new avenue to treating diabetes, researchers show that cells from the bone marrow give rise to insulin-producing cells in the pancreas of mice. These morphed cells actually produce the hormone insulin in response to glucose and display other characteristics demonstrating that they truly function as pancreas cells, according to a new study by researchers from NYU School of Medicine.
The study is published in the March 14 issue of the Journal of Clinical Investigation. The researchers caution that the findings cannot be applied to treating diabetics now, but may one day provide a means to produce unlimited quantities of functional insulin-producing cells culled from the bone marrow of diabetes patients. Since patients would produce their own cells for transplantation, it is possible that the cells would not be rejected by their immune system.
"Clearly much work remains to be done," says Mehboob A. Hussain, M.D., Assistant Professor of Medicine and Pharmacology, who led the study. "But I am absolutely excited by the potential applications of our findings," he says. "In our body, there is an additional, easily accessible source of cells that are capable of becoming insulin-producing pancreatic endocrine cells. Transplantation of bone marrow stem cells already is a routine procedure for treating cancer and other diseases, and we could build on that experience."
Dr. Hussain's study is described as "elegant" in an accompanying editorial by Drs. Vivian Lee and Markus Stoffel, two diabetes researchers from The Rockefeller University, published in the same issue of the journal. Dr. Hussain used a molecular biology technique called "CRE-loxP" that allowed him to identify and isolate bone marrow derived cells and to study them more closely than had previously been possible.
One of the longstanding goals of diabetes research is to find a way to replace the insulin-producing cells in the pancreas that are damaged or destroyed in some forms of diabetes. These cells are called beta cells and they are found in cell groups called islets of Langerhans in the pancreas. In recent years doctors have reported that they successfully transplanted pancreatic islets from cadavers into some severely ill diabetics, most of whom were subsequently freed from daily insulin shots. Insulin regulates blood sugar levels. Immunosuppressive drugs were required to prevent rejection of the transplants.
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However, the supply of islets from cadavers is extremely limited, so medical researchers are looking elsewhere. Several research groups have reported that embryonic stem cells and cells found in the pancreas (other than beta cells) could be converted into insulin-producing cells, but until now no one had specifically explored the bone marrow as a source of beta cells. (The bone marrow normally replenishes blood cells and in recent years researchers have shown that stem cells from the marrow can become cells of other organs.)
The CRE-loxP system is a sort of DNA editing technique that molecular biologists widely employ to engineer genes. In the new study, Dr. Hussain used the system to ingeniously create male mice with bone marrow cells that produce a protein called enhanced green fluorescent protein (EGFP) only in the presence of activated insulin genes, which are typically found in pancreatic beta cells. EGFP imparts a green glow to cells, which makes it easy to identify them. He then transplanted the bone marrow from these males into female mice whose bone marrow had been destroyed by radiation.
After four to six weeks, Dr. Hussain detected a small number of the glowing green cells in the pancreatic islets of Langerhans of the female mice. Further analysis showed that these cells came from the bone marrow and functioned as the insulin-producing beta cells. These cells all contained the Y chromosome, which could only have come from the male donor. The cells also secreted insulin in response to glucose, one of the signatures of pancreatic beta cells, and exhibited electrical activity and other properties of beta cells.
Moreover, a second set of experiments showed that these bone marrow derived cells were unlikely to be a result of cells fusing together. Some researchers have suggested that the conversion of stem cells into differentiated tissue is not real, but is due to artifacts of experimental design produced by the fusion of Y chromosome-bearing cells with host cells already present in the tissue. However, in the second set of experiments, Dr. Hussain used the CRE-loxP system to demonstrate that transplanted Y-chromosome bone marrow stem cells are not fusing with pancreas cells in female recipient mice.
Despite the promising results, there are caveats to the study. Only 1.7 to 3 percent of beta cells in the pancreas of the female mice came from transformed bone-marrow stem cells, a small number, and it isn't known which subpopulation of stem cells in the bone marrow are the actual source of insulin-producing cells. Furthermore, it isn't known what happens in diabetic mice after bone marrow transplantation. Dr. Hussain has proceeded with similar studies in diabetic mice and with experiments that could help clarify how bone marrow stem cells become beta cells in the pancreas.
"Our study isn't the final proof," says Dr. Hussain. "We still need to find out how well these converted cells are functioning compared to indigenous beta cells in the pancreas. A lot more work needs to be done. Nevertheless, our study demonstrates the potential for using the bone marrow as a source of insulin-producing cells."
The experiments in the study were performed at NYU School of Medicine and Dr. Hussain's co-authors are Drs. I. Andreea Ianus, George G. Holz and Neil D. Theise. The study was supported by grants from the National Institutes of Health, the American Diabetes Association, and the Juvenile Diabetes Research Foundation.
Source: NYU School of Medicine
