De Novo Formation of Insulin-Producing "Neo-β Cell Islets" from Intestinal Crypts

The ability to interconvert terminally differentiated cells could serve as a powerful tool for cell-based treatment of degenerative diseases, including diabetes mellitus. To determine which, if any, adult tissues are competent to activate an islet β cell program, we performed an invivo screen by expressing three β cell "reprogramming factors" in a wide spectrum of tissues. We report that transient intestinal expression of these factors-Pdx1, MafA, and Ngn3 (PMN)-promotes rapid conversion of intestinal crypt cells into endocrine cells, which coalesce into "neoislets" below the crypt base. Neoislet cells express insulin and show ultrastructural features of β cells. Importantly, intestinal neoislets are glucose-responsive and able to ameliorate hyperglycemia indiabetic mice. Moreover, PMN expression in human intestinal "organoids" stimulates the conversion of intestinal epithelial cells into β-like cells. Ourresults thus demonstrate that the intestine is anaccessible and abundant source of functional insulin-producing cells.