Immune-evasive human islet-like organoids ameliorate diabetes

Eiji Yoshihara, Carolyn O’Connor, Emanuel Gasser, Zong Wei, Tae Gyu Oh, Tiffany W. Tseng, Dan Wang, Fritz Cayabyab, Yang Dai, Ruth T. Yu, Christopher Liddle, Annette R. Atkins, Michael Downes, Ronald M. Evans

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)606-611
Number of pages6
JournalNature
Volume586
Issue number7830
DOIs
StatePublished - Oct 22 2020

ASJC Scopus subject areas

  • General

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