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Immune-evasive human islet-like organoids ameliorate diabetes

Author

Listed:
  • Eiji Yoshihara

    (Salk Institute for Biological Studies
    Harbor–UCLA Medical Center
    David Geffen School of Medicine at UCLA)

  • Carolyn O’Connor

    (Salk Institute for Biological Studies)

  • Emanuel Gasser

    (Salk Institute for Biological Studies)

  • Zong Wei

    (Salk Institute for Biological Studies
    Mayo Clinic)

  • 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
    Salk Institute for Biological Studies)

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.

Suggested Citation

  • 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 Dow, 2020. "Immune-evasive human islet-like organoids ameliorate diabetes," Nature, Nature, vol. 586(7830), pages 606-611, October.
    • Handle: RePEc:nat:nature:v:586:y:2020:i:7830:d:10.1038_s41586-020-2631-z
    DOI: 10.1038/s41586-020-2631-z
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    Cited by:

    1. Romana Bohuslavova & Valeria Fabriciova & Ondrej Smolik & Laura Lebrón-Mora & Pavel Abaffy & Sarka Benesova & Daniel Zucha & Lukas Valihrach & Zuzana Berkova & Frantisek Saudek & Gabriela Pavlinkova, 2023. "NEUROD1 reinforces endocrine cell fate acquisition in pancreatic development," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    2. Xiaojie Ma & Jie Cao & Ziyu Zhou & Yunkun Lu & Qin Li & Yan Jin & Guo Chen & Weiyun Wang & Wenyan Ge & Xi Chen & Zhensheng Hu & Xiao Shu & Qian Deng & Jiaqi Pu & Chengzhen Liang & Junfen Fu & Jianzhao, 2022. "N6-methyladenosine modification-mediated mRNA metabolism is essential for human pancreatic lineage specification and islet organogenesis," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    3. Yuqian Wang & Renqi Huang & Yougong Lu & Mingqi Liu & Ran Mo, 2024. "Immuno-protective vesicle-crosslinked hydrogel for allogenic transplantation," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    4. Chun Jing Wang & Lina Petersone & Natalie M. Edner & Frank Heuts & Vitalijs Ovcinnikovs & Elisavet Ntavli & Alexandros Kogimtzis & Astrid Fabri & Yassin Elfaki & Luke P. Houghton & Ralf J. Hosse & Dav, 2022. "Costimulation blockade in combination with IL-2 permits regulatory T cell sparing immunomodulation that inhibits autoimmunity," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    5. Zhuo Ma & Xiaofei Zhang & Wen Zhong & Hongyan Yi & Xiaowei Chen & Yinsuo Zhao & Yanlin Ma & Eli Song & Tao Xu, 2023. "Deciphering early human pancreas development at the single-cell level," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    6. Shenqiang Wang & Ying Zhang & Yanfang Wang & Yinxian Yang & Sheng Zhao & Tao Sheng & Yuqi Zhang & Zhen Gu & Jinqiang Wang & Jicheng Yu, 2023. "An in situ dual-anchoring strategy for enhanced immobilization of PD-L1 to treat autoimmune diseases," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    7. Marlie M. Maestas & Matthew Ishahak & Punn Augsornworawat & Daniel A. Veronese-Paniagua & Kristina G. Maxwell & Leonardo Velazco-Cruz & Erica Marquez & Jiameng Sun & Mira Shunkarova & Sarah E. Gale & , 2024. "Identification of unique cell type responses in pancreatic islets to stress," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    8. Keiichi Katsumoto & Siham Yennek & Chunguang Chen & Luis Fernando Delgadillo Silva & Sofia Traikov & Dror Sever & Ajuna Azad & Jingdong Shan & Seppo Vainio & Nikolay Ninov & Stephan Speier & Anne Grap, 2022. "Wnt4 is heterogeneously activated in maturing β-cells to control calcium signaling, metabolism and function," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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