Scripps Institute

Function of BMP4 and Id Proteins in the Expansion of Pancreatic Progenitors

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Type 1 diabetes results from destruction of insulin-producing beta cells. A possible treatment is to guide stem cells (pancreas progenitors) to differentiate into beta cells. This approach requires that we investigate the signals that cause them to proliferate. We are studying the effects of two proteins, Id and BMP4, in promoting proliferation of pancreas progenitors and/or beta cells. We found that BMP4 signaling is necessary for proliferation of pancreas progenitor cells, and this is correlated with an increase of Id expression. A possible source of pancreatic progenitor cells is thought to derive from pancreas epithelial duct cells. We have a transgenic mouse model (IFNgNOD), which expresses regenerating stem cells from the ducts. Importantly, we found that if we inject an antibody that inhibits BMP4 into these mice, this significantly reduced the number of proliferating duct cells.

Therefore, our results indicate that BMP4 and Id2 block the differentiation of endocrine progenitor cells and instead promote their expansion. During the first three weeks (in mouse) after birth, beta cells still have the capacity to proliferate. We are now studying the signals that are turned on during this period, including BMP4, so that we may extend it to use in expanding adult human islets for transplantation. The experiments proposed in this application provide novel insights into the signaling pathways that are required for expansion of pancreas progenitors and differentiated insulin-producing beta cells, hence provide a starting point towards improving the efficacy of treatments for patients and perhaps the prevention of clinical disease.