Human induced pluripotent stem cells as a source of insulin-producing cells for cell therapy of diabetes

BACKGROUND New sources of insulin-secreting cells are strongly required for the cure of diabetes. Recent successes in differentiating embryonic stem cells, in combination with the discovery that it is possible to derive human induced pluripotent stem cells (iPSC) from somatic cells, have raised the possibility that patient-specific β cells might be derived from patients through cell reprogramming and differentiation. AIMS In this study, we aimed to obtain insulin-producing cells from human iPSC and test their ability to secrete insulin in vivo. METHODS: Human iPSC, derived from both fetal and adult fibroblasts, were differentiated in vitro into pancreas-committed cells and their ability to secrete insulin was measured. iPSCderived cells at two different stages of differentiation (posterior foregut and endocrine cells) were transplanted into immunodeficient mice to test their ability to engraft, differentiate and secrete insulin. RESULTS: IPSC were shown to differentiate into insulin-producing cells in vitro, following the stages of pancreatic organogenesis. At the end of the differentiation, the production of INSULIN mRNA was highly increased and up to 14% of the cell population became insulin-positive. Terminally differentiated cells also produced C-peptide in vitro in both basal and stimulated conditions. In vivo, mice transplanted with pancreatic cells secreted human C-peptide in response to glucose stimulus, but transplanted cells were observed to lose insulin secretion capacity during the time. At histological evaluation, the grafts were composed of a mixed population of cells containing mature pancreatic cells, but also pluripotent cells and rare neuronal cells. CONCLUSION: These data overall suggest that human iPSC have the potential to generate insulinproducing cells and that these differentiated cells can engraft and secrete insulin in vivo.