@article{66b298d5086b4b58bbfeb09baf3799e1,
title = "Immune-evasive human islet-like organoids ameliorate diabetes",
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.",
author = "Eiji Yoshihara and Carolyn O{\textquoteright}Connor and Emanuel Gasser and Zong Wei and Oh, {Tae Gyu} and Tseng, {Tiffany W.} and Dan Wang and Fritz Cayabyab and Yang Dai and Yu, {Ruth T.} and Christopher Liddle and Atkins, {Annette R.} and Michael Downes and Evans, {Ronald M.}",
note = "Funding Information: Acknowledgements We thank J. Norris, H. Song, B. Henriquez, B. Collins and H. Juguilon for technical assistance; L. Ong and C. Brondos for administrative assistance; and M. Ahmadian and S. Liu for sharing materials and helpful discussion. scRNA-seq and ATAC–seq were supported by Next Generation Sequencing Core (N. Hah) of the Salk Institute and the UCSD IGM Genomics Center (K. Jepsen). Cell sorting and flow cytometry analyses, TEM and stem cell cultures were supported by the Flow Cytometry Core, the Waitt Advanced Biophotonics Core and the Stem Cell Core facilities at the Salk Institute, with funding from NIH-NCI CCSG: P30 014195, S10-OD023689, and the Waitt Foundation. R.M.E. is an investigator of the Howard Hughes Medical Institute at the Salk Institute and March of Dimes Chair in Molecular and Developmental Biology. This work is supported by grants from CIRM (DISC2-11175), NIH (1RO1DK120480-01), the Glenn Foundation for Medical Research, the Leona M. and Harry B. Helmsley Charitable Trust (2017-PG-MED001), Ipsen/Biomeasure, and by a gift from Steven and Lisa Altman. C.L. and M.D. are funded by grants from the National Health and Medical Research Council of Australia Project (512354, 632886, and 1043199). E.Y. is supported by DRC P&F grant (P30 DK063491), and Z.W. is supported by NIH (1K01DK120808). We dedicate this work to the memory of our inspirational friend and colleague Maryam Ahmadian.",
year = "2020",
month = oct,
day = "22",
doi = "10.1038/s41586-020-2631-z",
language = "English (US)",
volume = "586",
pages = "606--611",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7830",
}