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bioRxiv · 10.1101/2022.12.15.520488

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.
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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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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. Restoring glucose homeostasis with stomach-derived human insulin-secreting organoids. https://doi.org/10.1101/2022.12.15.520488

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