Generation of Functional Beta-Like Cells from Human Exocrine Pancreas

• DOI: 10.1371/journal.pone.0156204
• Publication Date: 2016-05-31T13:35:37Z
• Authors: Maria J. Lima; Kenneth R. Muir; Hilary M. Docherty; Neil W. A. McGowan; Shareen Forbes; Yves Heremans; Harry Heimberg; John Casey; Kevin Docherty
• Keywords: PDX1; PAX4; Proinsulin; NeuroD; Reprogramming

Transcription factor mediated lineage reprogramming of human pancreatic exocrine tissue could conceivably provide an unlimited supply islets for transplantation in the treatment diabetes. Exocrine can be efficiently reprogrammed to islet-like cells using a cocktail transcription factors: Pdx1, Ngn3, MafA and Pax4 combination with growth factors. We show here that overexpression exogenous suppression endogenous ARX considerably enhances production functional insulin-secreting β-like concomitant α-cells. The efficiency was further increased by culture on laminin-coated plates media containing low glucose concentrations. Immunocytochemistry revealed cultures were composed ~45% clusters comprising >80% monohormonal insulin+ cells. resultant expressed insulin protein levels at ~15-30% adult islets, processed proinsulin packaged into secretory granules, exhibited responsive secretion, had immediate prolonged effect normalising blood upon diabetic mice. estimate approximately 3 billion these would have therapeutic following engraftment type 1 diabetes patients one pancreas sufficient numerous transplants.