Journal
NATURE
Volume 586, Issue 7830, Pages 606-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41586-020-2631-z
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Funding
- Salk Institute
- UCSD IGM Genomics Center
- NIH-NCI CCSG [P30 014195, S10-OD023689]
- Waitt Foundation
- CIRM [DISC2-11175]
- NIH [1RO1DK120480-01, 1K01DK120808]
- Glenn Foundation for Medical Research
- Leona M. and Harry B. Helmsley Charitable Trust [2017-PG-MED001]
- Ipsen/Biomeasure
- National Health and Medical Research Council of Australia [512354, 632886, 1043199]
- DRC PF grant [P30 DK063491]
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Islets derived from stem cells hold promise as a therapy for insulin-dependent diabetes, but there remain challenges towards achieving this goal(1-6). Here we generate human islet-like organoids (HILOs) from induced pluripotent stem cells and show that non-canonical WNT4 signalling drives the metabolic maturation necessary for robust ex vivo glucose-stimulated insulin secretion. These functionally mature HILOs contain endocrine-like cell types that, upon transplantation, rapidly re-establish glucose homeostasis in diabetic NOD/SCID mice. Overexpression of the immune checkpoint protein programmed death-ligand 1 (PD-L1) protected HILO xenografts such that they were able to restore glucose homeostasis in immune-competent diabetic mice for 50 days. Furthermore, ex vivo stimulation with interferon-gamma induced endogenous PD-L1 expression and restricted T cell activation and graft rejection. The generation of glucose-responsive islet-like organoids that are able to avoid immune detection provides a promising alternative to cadaveric and device-dependent therapies in the treatment of diabetes. Metabolically-mature human islet-like organoids generated from induced pluripotent stem cells are able to recapitulate insulin-responsive pancreatic islet function and avoid immunologic cell death in diabetic mouse transplantation models.
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