Suppression of Epithelial-to-Mesenchymal Transitioning Enhances Ex Vivo Reprogramming of Human Exocrine Pancreatic Tissue Toward Functional Insulin-Producing

Because of the lack of tissue available for islet transplantation, new sources of b-cells have been sought for the treatment of type 1 diabetes. The aim of this study was to determine whether the human exocrine-enriched fraction from the islet isolation proce-dure could be reprogrammed to provide additional islet tissue for transplantation. The exocrine-enriched cells rapidly dedifferenti-ated in culture and grew as a mesenchymal monolayer. Genetic lineage tracing confirmed that these mesenchymal cells arose, in part, through a process of epithelial-to-mesenchymal transition-ing (EMT). A protocol was developed whereby transduction of these mesenchymal cells with adenoviruses containing Pdx1, Ngn3, MafA, and Pax4 generated a population of cells that were enriched in glucagon-secreting a-like cells. Transdifferentiation or reprogramming toward insulin-secreting b-cells was enhanced, however, when using unpassaged cells in combination with inhi