Chromatin-remodeling factors allow differentiation of bone marrow cells into insulin-producing cells

Type 1 diabetes is caused by the destruction of pancreatic beta- cells by T cells of the immune system. Islet transplantation is a promising therapy for diabetes mellitus. Bone marrow stem cells ( BMSC) have the capacity to differentiate into various cell lineages including endocrine cells of the pancreas. To investigate the conditions that allow BMSC to differentiate into insulin-producing cells, a novel in vitro method was developed by using the histone deacetylase inhibitor, trichostatin A ( TSA). BMSC, cultured in presence of TSA, differentiated into isletlike clusters under appropriate culture conditions. These isletlike clusters were similar to the cells of the islets of the pancreas. The islet- like clusters showed endocrine gene expression typical for pancreatic beta- cell development and function, such as insulin ( I and II), glucagon, somatostatin, GLUT- 2, pancreatic duodenal homeobox-1 ( PDX-1), and Pax 4. Immunocytochemistry confirmed islet- like clusters contained pancreatic hormones. The colocalization of insulin and C-peptide was also observed. Enzyme-linked immunosorbent assay analysis demonstrated that insulin secretion was regulated by glucose. Western blot analysis demonstrated the presence of stored insulin. Electron microscopy of the islet- like cells revealed an ultrastructure similar to that of pancreatic beta-cells, which contain insulin granules within secretory vesicles. These findings suggest that histone- deacetylating agents could allow the differentiation of BMSC into insulin- producing beta-cells.