Dr. Michael German of UCSF presented Wednesday night as part of UCSF's "Mini Medical School" series, updating us on the progress his lab has made in differentiating an embryonic stem cell into an insulin-secreting islet cell. Dr. German explained that with current islet cell transplantation, most grafts fail after one year; while there is a 90% success rate, defined as immediate success in getting the patient off of insulin, there is only a 10% 5-year success rate.
Of course, because the islet cell transplantation procedure is so minimally invasive--the islets are injected with a long needle into the hepatic portal vein--this procedure could be repeated annually. The major barrier is that the supply of islet cells is limited, as no islet cells can be taken from a live donor. Estimates suggest that if every possible pancreas were recovered from cadavers, there would be a maximum of 5,000 per year available, which pales in comparison to the 50,000 new cases of diabetes diagnosed each year. Relatedly, part of the reason for the high failure rate is that only a few cells are transplanted; more successful procedures have used islets from 2-3 pancreases per patient, and Dr. German said that transplating even more, on the order of the equivalent of 4-6 pancreases, may lead to lower failure rates. The promise of embryonic stem cell research is that it could provide an unlimited source of islet cells.
Dr. German's lab is working on understanding the factors that influence differentation. Embryonic stem cells can be induced to differentiate first to endoderm, then to pancreatic progenitors, then to endocrine/islet progenitors,and finally to beta cell progenitors and beta cells. A number of critical transcription factors have been identified, including PDX-1 and neurogenin 3. It is especially difficult to differentiate cells into endoderm, and investigators were first successful in this one year ago. Dr. German believes that in the next year, investigators will have success in deriving an insulin-producing beta cell from an embryonic stem cell. He noted that embryonic stem cell therapy has an advantage in diabetes, because transplantation of this type of cells has already been done; once cells are produced, they can be immediately used in patients. Of course, patients will most likely need to be on immunosuppressive drugs. Alternatively, stem cells could be created that match the patient's DNA--so-termed therapeutic cloning--but experiments have shown that autoimmunity recurs, within days, when islet cells are transplanted between identical twins.
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