Modeling in vivo induction of gastric insulin-secreting cells using transplanted human stomach organoids

Insulin-dependent diabetes could be treated by supplying patients with primary pancreatic islets or other types of insulin-secreting cells. Functional insulin+ cells can be induced in situ from the murine stomach using defined genetic factors, offering a potential method to directly produce autologous insulin+ cells. Here, we modeled whether such gastric insulin-secreting (GINS) cells could be generated in vivo from human stomach tissues. We produced human gastric organoids (hGOs) from human embryonic stem cells engineered with inducible expression of reprogramming factors. The hGOs were stably transplanted for 6 months and showed robust cytodifferentiation resembling the human stomach in structure and cellular composition. Upon hGO maturation in vivo, we activated the reprogramming factors and observed formation of insulin+ cells, which secreted insulin into the circulation and ameliorated experimental diabetes. Our modeling indicates that GINS cells can be induced from human stomach tissues in vivo, warranting further therapeutic development for this technology. This study aimed at providing insights into the cell identities of human gastric organoids overexpressing NPM factors. Single-cell RNA sequencing was employed to analyze the transcriptomes of ECAD+ epithelial cells from human gastric organoids treated for 10 days with doxycycline.