Open AccessImmune-evasive human islet-like organoids ameliorate diabetes
Author(s) -
Ellen 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
Publication year - 2020
Publication title -
nature
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 15.993
H-Index - 1226
eISSN - 1476-4687
pISSN - 0028-0836
DOI - 10.1038/s41586-020-2631-z
Subject(s) - organoid , induced pluripotent stem cell , glucose homeostasis , islet , immune system , transplantation , biology , stem cell , ex vivo , microbiology and biotechnology , cancer research , progenitor cell , insulin , immunology , endocrinology , medicine , in vivo , embryonic stem cell , insulin resistance , biochemistry , gene
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-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.