Title | Stomach-derived human insulin-secreting organoids restore glucose homeostasis. |
Publication Type | Journal Article |
Year of Publication | 2023 |
Authors | Huang 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 |
Journal | Nat Cell Biol |
Date Published | 2023 Apr 27 |
ISSN | 1476-4679 |
Abstract | 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. |
DOI | 10.1038/s41556-023-01130-y |
Alternate Journal | Nat Cell Biol |
PubMed ID | 37106062 |
PubMed Central ID | 3912826 |
Grant List | P30 DK034854 / DK / NIDDK NIH HHS / United States R01 DK125817 / DK / NIDDK NIH HHS / United States P30 DK034854 / DK / NIDDK NIH HHS / United States |