Cited by 333Pancreatic function and diabetesPluripotent Stem Cells ResearchDiabetes and associated disorders

Immune-evasive human islet-like organoids ameliorate diabetes

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Yoshihara, Eiji, O’Connor, Carolyn, Gasser, Emanuel, Wei, Zong, Oh, Tae Gyu, Tseng, Tiffany W., Wang, Dan, Cayabyab, Fritz +6 more·2020·Nature

Abstract

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.

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  • Islet-like organoids made from hiPSCs directly overexpressing PD-L1 using a lentiviral system were found to evade the immune system in both immune-competent mice and in a humanized mouse model.

    “This PD-L1 strategy was pushed even further by directly overexpressing PD-L1 in islet-like organoids made from hiPSCs using a lentiviral system.67 These engineered cells were found to evade the immune system in both immune-competent mice and in a humanized mouse model.”

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Authors
Yoshihara, E., O’Connor, C., Gasser, E., Wei, Z., Oh, T. G., Tseng, T. W., Wang, D., Cayabyab, F., Dai, Y., Yu, R. T., Liddle, C., Atkins, A. R., Downes, M., & Evans, R. M.
Affiliations
  • Salk Institute for Biological Studies (US)
  • The University of Sydney (AU)
Corresponding author
Evans, Ronald M.
Venue
Nature
Published
2020-08-19
Volume
586
Issue
7830
Pages
606-611
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
OpenAlex
W3068518905
Cited by
333
References
44
Citations by year
2026: 28 · 2025: 63 · 2024: 64 · 2023: 46 · 2022: 71 · 2021: 53 · 2020: 8
FWCI
40.67
Type
journal article
Language
en
Open access
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • Howard Hughes Medical Institute
  • National Institutes of Health (1s10od023689-01a1)
  • National Cancer Institute (P30CA014195)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK120480, K01DK120808, P30DK063491)
  • National Institute of Environmental Health Sciences (P42ES010337)
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
Keywords
type 1 diabetes, induced pluripotent stem cells, glucose-stimulated insulin secretion, PD-L1, immune evasion, islet transplantation, graft rejection, interferon-gamma, T cell activation, glucose homeostasis, NOD/SCID mice
MeSH terms
Insulin Secretion, Animals, Cell Line, Diabetes Mellitus, Experimental, Female, Glucose, Graft Rejection, Homeostasis, Humans, Immune Tolerance, Islets of Langerhans, Lymphocyte Activation, Male, Organoids, T-Lymphocytes, Islets of Langerhans Transplantation, Mice, SCID, Mice, Inbred NOD, Epigenesis, Genetic, Mice, Immune Evasion, Wnt Signaling Pathway, Wnt4 Protein, B7-H1 Antigen, Heterografts

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