Stomach-derived human insulin-secreting organoids restore glucose homeostasis.

TitleStomach-derived human insulin-secreting organoids restore glucose homeostasis.
Publication TypeJournal Article
Year of Publication2023
AuthorsHuang X, Gu W, Zhang J, Lan Y, Colarusso JL, Li S, Pertl C, Lu J, Kim H, Zhu J, Breault DT, Sévigny J, Zhou Q
JournalNat Cell Biol
Date Published2023 Apr 27

Gut stem cells are accessible by biopsy and propagate robustly in culture, offering an invaluable resource for autologous cell therapies. Insulin-producing cells can be induced in mouse gut, but it has not been possible to generate abundant and durable insulin-secreting cells from human gut tissues to evaluate their potential as a cell therapy for diabetes. Here we describe a protocol to differentiate cultured human gastric stem cells into pancreatic islet-like organoids containing gastric insulin-secreting (GINS) cells that resemble β-cells in molecular hallmarks and function. Sequential activation of the inducing factors NGN3 and PDX1-MAFA led human gastric stem cells onto a distinctive differentiation path, including a SOX4High endocrine and GalaninHigh GINS precursor, before adopting β-cell identity, at efficiencies close to 70%. GINS organoids acquired glucose-stimulated insulin secretion in 10 days and restored glucose homeostasis for over 100 days in diabetic mice after transplantation, providing proof of concept for a promising approach to treat diabetes.

Alternate JournalNat Cell Biol
PubMed ID37106062
PubMed Central ID3912826
Grant ListP30 DK034854 / DK / NIDDK NIH HHS / United States
R01 DK125817 / DK / NIDDK NIH HHS / United States
P30 DK034854 / DK / NIDDK NIH HHS / United States