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

• DOI: 10.2337/db12-1256
• Publication Date: 2013-04-23T08:25:44Z
• Authors: Maria João Lima; Kenneth R. Muir; Hilary M. Docherty; Robert Drummond; Neil W.A. McGowan; Shareen Forbes; Yves Heremans; Isabelle Houbracken; James A. Ross; Stuart J. Forbes; Philippe Ravassard; Harry Heimberg; John Casey; Kevin Docherty
• Keywords: Transdifferentiation; PDX1; Reprogramming; PAX4

Because of the lack tissue available for islet transplantation, new sources β-cells have been sought treatment type 1 diabetes. The aim this study was to determine whether human exocrine-enriched fraction from isolation procedure could be reprogrammed provide additional transplantation. cells rapidly dedifferentiated in culture and grew as a mesenchymal monolayer. Genetic lineage tracing confirmed that these arose, part, through process epithelial-to-mesenchymal transitioning (EMT). A protocol developed whereby transduction with adenoviruses containing Pdx1, Ngn3, MafA, Pax4 generated population were enriched glucagon-secreting α-like cells. Transdifferentiation or reprogramming toward insulin-secreting enhanced, however, when using unpassaged combination inhibition EMT by inclusion Rho-associated kinase (ROCK) transforming growth factor-β1 inhibitors. Resultant able secrete insulin response glucose on transplantation normalize blood levels streptozotocin diabetic NOD/SCID mice. In conclusion, can best achieved fresh material under conditions is inhibited, rather than allowing expand