Generating functional insulin-secreting cells is a major goal of developing cell therapies for diabetes. Studies have shown that insulin+ cells can be derived from non-beta cells by cellular reprogramming. We carried out a genetic screen in mouse to identify adult cell types amenable for direct conversion to insulin+ cells by a cocktail of reprogramming factors (Ngn3, Pdx1, and Mafa, termed NPM factors). Surprisingly, the antral stomach epithelial cells were found to possess previously unappreciated ability for conversion into functional insulin+ cells. The induced gastric insulin+ cells have molecular and functional hallmarks of pancreatic beta cells, can secrete insulin in response to high glucose, and suppress hyperglycemia in an experimental form of diabetes. Compared with antral stomach, conversion of intestinal tissue to insulin+ cells is less complete partly due to persistence of the intestinal cell fate regulator Cdx2, which serves as a molecular barrier for reprogramming. Importantly, the gastric insulin+ cells can be readily regenerated from gastric epithelium in vivo, thus providing a renewable source of new insulin+ cells.
To evaluate whether human gastric tissues can be reprogrammed into functional insulin+ cells. We generated human antral stomach mini-organs (hGOs) from human embryonic stem cells (hESCs) by step-wise differentiation. The hGOs possess all the major epithelial and mesenchymal cell types of human antral stomach. We genetically engineered the hES cells, and consequently, the hGOs for inducible expression of NPM factors. Our studies showed that hGOs can be transplanted and remain stable in vivo for at least 6 months. Activation of NPM factors led to induction of insulin+ cells in hGOs, insulin secretion into circulation, and amelioration of experimental diabetes. These studies highlight the potential of engineered human stomach mini-organs as a new transplantable material for glycemic control.