Engineered stomach tissue as a renewable source of functional beta-cells for blood glucose regulation. Mus musculus

The gastrointestinal (GI) epithelium is a highly regenerative tissue with the potential to provide a renewable source of insulin+ cells using cellular reprogramming. Here, we 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 beta-cells. Expression of beta-cell reprogramming factors in vivo converts antral cells efficiently into insulin+ cells with close molecular and functional resemblance to beta-cells. Our data further indicate that the intestine-expressed Cdx2 acts as a molecular barrier for beta-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 beta-cells for glycemic control. Overall design: Total RNA extracted from primary mouse tissues: Stomach (3 replicates), Duodenum (3 replicates) and Colon (2 replicates)