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Restoring glucose homeostasis with stomach-derived human insulin-secreting organoids

Huang, X.; Gu, W.; Zhang, J.; Lan, Y.; Colarusso, J. L.; Li, S.; Pertl, C.; Lu, J.; Kim, H.; Zhu, J.; Sevigny, J.; Zhou, Q.

2022-12-16 cell biology
10.1101/2022.12.15.520488 bioRxiv
Show 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 (hGSCs) into pancreatic islet-like organoids containing gastric insulin-secreting (GINS) cells that resemble {beta}-cells in molecular hallmarks and function. Sequential activation of the inducing factors NGN3 and PDX1-MAFA led hGSCs onto a novel differentiation path, including a SOX4High endocrine and GalaninHigh GINS precursor, before adopting {beta}-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 new approach to treat diabetes.

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"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.