The gastrointestinal (GI) epithelium is a highly regenerative tissue with the potential to provide a renewable source of insulin+ cells using cellular reprogramming. Here, I describe the antral stomach as a previously unrecognized source highly amenable to conversion into functional insulin-secreting cells. Native antral endocrine cells share a surprising degree of transcriptional similarity with pancreatic β cells. Expression of β-cell reprogramming factors (Ngn3, Pdx1, and Mafa) in vivo converts antral cells efficiently into insulin+ cells with close molecular and functional resemblance to endogenous β cells. My data further indicate that Cdx2, an intestine-specific transcription factor, acts as a molecular barrier for β-cell conversion. Induced GI insulin+ cells can suppress hyperglycemia over at least 6 months, and they regenerate rapidly after ablation from the native stem-cell compartment. Transplantation of bioengineered stomach mini-organs also produced insulin+ cells and suppressed hyperglycemia. These studies demonstrate the potential of developing engineered stomach tissue as a renewable source of functional β cells for glycemic control.
