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 and Ronald M. Evans ()
Additional contact information
Eiji Yoshihara: Salk Institute for Biological Studies
Carolyn O’Connor: Salk Institute for Biological Studies
Emanuel Gasser: Salk Institute for Biological Studies
Zong Wei: Salk Institute for Biological Studies
Tae Gyu Oh: Salk Institute for Biological Studies
Tiffany W. Tseng: Salk Institute for Biological Studies
Dan Wang: Salk Institute for Biological Studies
Fritz Cayabyab: Salk Institute for Biological Studies
Yang Dai: Salk Institute for Biological Studies
Ruth T. Yu: Salk Institute for Biological Studies
Christopher Liddle: University of Sydney
Annette R. Atkins: Salk Institute for Biological Studies
Michael Downes: Salk Institute for Biological Studies
Ronald M. Evans: Salk Institute for Biological Studies

Nature, 2020, vol. 586, issue 7830, 606-611

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41586-020-2631-z

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