Immune-evasive human islet-like organoids ameliorate diabetes
- PMID: 32814902
- PMCID: PMC7872080
- DOI: 10.1038/s41586-020-2631-z
Immune-evasive human islet-like organoids ameliorate diabetes
Erratum in
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Publisher Correction: Immune-evasive human islet-like organoids ameliorate diabetes.Nature. 2021 Feb;590(7844):E27. doi: 10.1038/s41586-020-03109-3. Nature. 2021. PMID: 33469222 Free PMC article. No abstract available.
Abstract
Islets derived from stem cells hold promise as a therapy for insulin-dependent diabetes, but there remain challenges towards achieving this goal1-6. 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-γ 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.
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Comment in
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Type 1 diabetes mellitus: another step closer to pancreatic β-cell transplantation.Nat Rev Endocrinol. 2020 Nov;16(11):623. doi: 10.1038/s41574-020-00417-6. Nat Rev Endocrinol. 2020. PMID: 32879466 No abstract available.
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Solving the Puzzle of Immune Tolerance for β-Cell Replacement Therapy for Type 1 Diabetes.Cell Stem Cell. 2020 Oct 1;27(4):505-507. doi: 10.1016/j.stem.2020.09.008. Cell Stem Cell. 2020. PMID: 33007232
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