IN-VITRO GENERATION OF ISLETS IN LONG-TERM CULTURES OF PLURIPOTENT STEM-CELLS FROM ADULT-MOUSE PANCREAS

Pancreatic islets of Langerhans exhibit an architecture and cellular o rganization ideal for rapid, yet finely controlled, responses to chang es in blood glucose levels. In type I, insulin-dependent diabetes (IDD ), this organization is lost as a result of the progressive autoimmune response which selectively destroys the insulin-producing pancreatic beta cells. Since beta cells are perceived as end-stage differentiated cells having limited capacity for regeneration in situ, individuals w ith IDD resulting from beta cell loss or dysfunction require life-long insulin therapy. Efforts to produce islet neogenesis or initiate isle t growth in vitro from either fetal or adult tissue have had minimal s uccess. We now report that pancreatic-derived, pluripotent islet-produ cing stem cells (IPSCs), isolated from prediabetic mice, can be grown in longterm cultures and differentiated into immature functional islet -like structures containing cells which express low levels of insulin, glucagon and/or somatostatin. When such in vitro grown islets were im planted into clinically diabetic NOD mice, the implanted mice were suc cessfully weaned from insulin long-term (>50 days) without ill effects . The implanted mice maintained blood glucose levels just above euglyc emic (180-220 mg/dl) and showed no signs of disease. Thus, this techni cal breakthrough provides new therapeutic approaches to diabetes as an alternative to insulin therapy.