Article

Interspecies organogenesis generates autologous functional islets

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Abstract

Islet transplantation is an established therapy for diabetes. We have previously shown that rat pancreata can be created from rat pluripotent stem cells (PSCs) in mice through interspecies blastocyst complementation. Although they were functional and composed of rat-derived cells, the resulting pancreata were of mouse size, rendering them insufficient for isolating the numbers of islets required to treat diabetes in a rat model. Here, by performing the reverse experiment, injecting mouse PSCs into Pdx-1-deficient rat blastocysts, we generated rat-sized pancreata composed of mouse-PSC-derived cells. Islets subsequently prepared from these mouse–rat chimaeric pancreata were transplanted into mice with streptozotocin-induced diabetes. The transplanted islets successfully normalized and maintained host blood glucose levels for over 370 days in the absence of immunosuppression (excluding the first 5 days after transplant). These data provide proof-of-principle evidence for the therapeutic potential of PSC-derived islets generated by blastocyst complementation in a xenogeneic host.

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Acknowledgements

We thank A. Oshima and H. Tsukui for technical support, K. Okada for secretarial support, H. Nagashima and M. Watanabe for advice in preparing the manuscript, A. S. Knisely for reading of the manuscript and Japan Insulin-Dependent Diabetes Mellitus (IDDM) Network for continuous support. This work was supported by grants from Japan Science and Technology Agency, Exploratory Research for Advanced Technology, Leading Advanced Projects for medical innovation, Japan Agency for Medical Research and Development, Japan Society for the Promotion of Science, KAKENHI Grant Number 26460358, research grant for type 1 diabetes, Japan IDDM Network and California Institute for Regenerative Medicine.

Author information

Author notes

    • Tomoyuki Yamaguchi
    •  & Hideyuki Sato

    These authors contributed equally to this work.

Affiliations

  1. Division of Stem Cell Therapy, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan

    • Tomoyuki Yamaguchi
    • , Hideyuki Sato
    • , Megumi Kato-Itoh
    • , Naoaki Mizuno
    • , Toshihiro Kobayashi
    • , Ayaka Yanagida
    • , Ayumi Umino
    • , Sanae Hamanaka
    • , Hideki Masaki
    •  & Hiromitsu Nakauchi
  2. Center for Genetic Analysis of Behavior, National Institute for Physiological Sciences, Okazaki, Aichi, Japan

    • Teppei Goto
    • , Hiromasa Hara
    • , Makoto Sanbo
    •  & Masumi Hirabayashi
  3. Department of Pathology, Research Hospital, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan

    • Yasunori Ota
  4. Centre of Stem Cells and Regenerative Medicine and Institute of Liver Studies, King’s College London, UK

    • Sheikh Tamir Rashid
  5. Institute for Stem Cell Biology and Regenerative Medicine, Department of Genetics, Stanford University School of Medicine, Stanford, California, USA

    • Sheikh Tamir Rashid
    •  & Hiromitsu Nakauchi

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Contributions

T.Y. and H.S. designed, performed, and analysed all experiments and wrote the manuscript. M.I.-K., T.G., H.H., M.S., T.K., A.Y., and A.U. performed embryo manipulation. N.M. performed data analysis. Y.O. performed histopathological analysis. S.H. performed establishment of iPSCs. H.M. performed data analysis. D.T.R. wrote the manuscript. M.H. performed embryo manipulation and data analysis. H.N. designed the study and wrote the manuscript.

Competing interests

H.N. is a co-founder and shareholder of iCELL Inc., ChimaERA Corporation and ReproCELL Inc.

Corresponding author

Correspondence to Hiromitsu Nakauchi.

Reviewer Information Nature thanks H. Lickert, Q. Zhou and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Extended data