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Title: Immune-evasive human islet-like organoids ameliorate diabetes.

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

Published In Nature, (2020 Oct)

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.

PubMed ID: 32814902 Exiting the NIEHS site

MeSH Terms: Animals; B7-H1 Antigen/genetics; B7-H1 Antigen/metabolism; Cell Line; Diabetes Mellitus, Experimental/immunology*; Diabetes Mellitus, Experimental/pathology*; Epigenesis, Genetic; Female; Glucose/metabolism; Graft Rejection; Heterografts; Homeostasis; Humans; Immune Evasion*; Immune Tolerance; Insulin Secretion; Islets of Langerhans Transplantation; Islets of Langerhans/cytology*; Islets of Langerhans/immunology*; Lymphocyte Activation; Male; Mice; Mice, Inbred NOD; Mice, SCID; Organoids/cytology*; Organoids/immunology*; Organoids/transplantation; T-Lymphocytes/cytology; T-Lymphocytes/immunology; Wnt Signaling Pathway/drug effects; Wnt4 Protein/metabolism; Wnt4 Protein/pharmacology

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