Notch Signaling as Gatekeeper of Rat Acinar-to-β-Cell Conversion in Vitro

Abstract

Background & Aims: Exocrine acinar cells in the pancreas are highly differentiated cells that retain a remarkable degree of plasticity. After isolation and an initial phase of dedifferentiation in vitro, rodent acinar cells can convert to endocrine β-cells when cultured in the presence of appropriate factors. The mechanisms regulating this phenotypic conversion are largely unknown. Methods: Using rat acinar cell cultures, we studied the role of Notch signaling in a model of acinar-to-β-cell conversion. Results: We report a novel lectin-based cell labeling method to demonstrate the acinar origin of newly formed insulin-expressing β-cells. This method allows for specific tracing of the acinar cells. We demonstrate that growth factor-induced conversion of adult acinar cells to β-cells is negatively regulated by Notch1 signaling. Activated Notch1 signaling prevents the reexpression of the proendocrine transcription factor Neurogenin-3, the key regulator of endocrine development in the embryonic pancreas. Interfering with Notch1 signaling allows modulating the acinar cell susceptibility to the differentiation-inducing factors. Its inhibition significantly improves β-cell neoformation with approximately 30% of acinar cells that convert to β-cells. The newly formed β-cells mature when transplanted ectopically and are capable of restoring normal blood glycemia in diabetic recipients. Conclusions: We report for the first time an efficient way to reprogram one third of the acinar cells to β-cells by adult cell type conversion. This could find application in cell replacement therapy of type 1 diabetes, provided that it can be translated from rodent to human models. © 2009 AGA Institute.