Curative treatment of type 1 diabetes mellitus by islet transplantation is limited by insufficient numbers of donor organs. Alternative sources for pancreatic cells may circumvent this problem. Our preliminary findings suggest that bone marrow (BM) contains pluripotent cells that are capable of engrafting pancreatic islets and secreting insulin. We have devised an in vivo mouse model of bone marrow transplantation in which donor derived cells that express insulin can be identified by their expression of enhanced green fluorescent protein (EGFP). Donor-derived cells can be isolated and enriched by fluorescence activated cell sorting and further tested in vitro. We hypothesize that bone marrow contains a subpopulation of cells that has the capacity to differentiate into pancreatic endocrine beta-cells and that these are fully differentiated and functionally competent. Our initial aims are: (1) To assess whether BM derived beta-cells exhibit characteristics of mature functionally competent beta-cells. Processing of pro-insulin to insulin and C-peptide will be assessed in these cells. Studies of the responsiveness to glucose, to the incretin-hormone glucagon-like peptide-1 in cultured BM derived EGFP-positive islet cells will be conducted. Electrophysiological properties of calcium and ATP-sensitive potassium channels will be determined using the patch-clamp technique. Morphological characterization of insulin secretory granules at the ultrastructural level will complement these studies. (2) To evaluate the kinetics and underlying mechanisms of """"""""transdifferentiation"""""""" of BM derived cells into pancreatic endocrine cells and to find strategies to increase the relative quantity of this """"""""transdifferentiation"""""""" process. (3) To test whether diabetic mouse models can be successfully treated with bone marrow transplantation. (4) To identify the cell type within BM that contributes to the pancreatic endocrine cell population. The long-term goal of these studies is to evaluate transplantation of BM derived cells as a potential treatment for diabetes mellitus.
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