IDEAS home Printed from https://ideas.repec.org/a/nat/nature/v586y2020i7830d10.1038_s41586-020-2631-z.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41586-020-2631-z
    File Function: Abstract
    Download Restriction: Access to the full text of the articles in this series is restricted.
    File URL: https://libkey.io/10.1038/s41586-020-2631-z?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    As the access to this document is restricted, you may want to search for a different version of it.

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. 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.
    2. 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.
    3. 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.
    4. 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.
    5. 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.
    6. 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.
    7. 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.
    8. 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.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:nature:v:586:y:2020:i:7830:d:10.1038_s41586-020-2631-z. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.