Reprogrammed Stomach Tissue as a Renewable Source of Functional β Cells for Blood Glucose Regulation

•Antral stomach cells reprogram effectively to insulin+ pancreatic β-like cells•Antral endocrine cells are transcriptionally related to pancreatic β cells•Induced insulin+ cells reverse hypoglycemia after transplantation in diabetic mice•Reprogrammed cells in bioengineered mini-organs give functional rescue in vivo

SummaryThe gastrointestinal (GI) epithelium is a highly regenerative tissue with the potential to provide a renewable source of insulin+ cells after undergoing cellular reprogramming. Here, we show that cells of the antral stomach have a previously unappreciated propensity for conversion into functional insulin-secreting cells. Native antral endocrine cells share a surprising degree of transcriptional similarity with pancreatic β cells, and expression of β cell reprogramming factors in vivo converts antral cells efficiently into insulin+ cells with close molecular and functional similarity to β cells. Induced GI insulin+ cells can suppress hyperglycemia in a diabetic mouse model for at least 6 months and regenerate rapidly after ablation. Reprogramming of antral stomach cells assembled into bioengineered mini-organs in vitro yielded transplantable units that also suppressed hyperglycemia in diabetic mice, highlighting the potential for development of engineered stomach tissues as a renewable source of functional β cells for glycemic control.

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