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Immune-evasive human islet-like organoids ameliorate diabetes
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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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“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.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [67]
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Metadata
- 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.
- ORCID
- Venue
- Nature
- Published
- 2020-08-19
- Volume
- 586
- Issue
- 7830
- Pages
- 606-611
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC7872080
- 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
- Update notices
- correction (2021-01-19)
- Open access
- green
- www.ncbi.nlm.nih.gov
- 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 › Endocrinology, Diabetes and Metabolism › 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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