• A Corrigendum to this article was published on 06 April 2016

This article has been updated

Abstract

The transplantation of glucose-responsive, insulin-producing cells offers the potential for restoring glycemic control in individuals with diabetes1. Pancreas transplantation and the infusion of cadaveric islets are currently implemented clinically2, but these approaches are limited by the adverse effects of immunosuppressive therapy over the lifetime of the recipient and the limited supply of donor tissue3. The latter concern may be addressed by recently described glucose-responsive mature beta cells that are derived from human embryonic stem cells (referred to as SC-β cells), which may represent an unlimited source of human cells for pancreas replacement therapy4. Strategies to address the immunosuppression concerns include immunoisolation of insulin-producing cells with porous biomaterials that function as an immune barrier5,6. However, clinical implementation has been challenging because of host immune responses to the implant materials7. Here we report the first long-term glycemic correction of a diabetic, immunocompetent animal model using human SC-β cells. SC-β cells were encapsulated with alginate derivatives capable of mitigating foreign-body responses in vivo and implanted into the intraperitoneal space of C57BL/6J mice treated with streptozotocin, which is an animal model for chemically induced type 1 diabetes. These implants induced glycemic correction without any immunosuppression until their removal at 174 d after implantation. Human C-peptide concentrations and in vivo glucose responsiveness demonstrated therapeutically relevant glycemic control. Implants retrieved after 174 d contained viable insulin-producing cells.

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Change history

  • 18 February 2016

    In the version of this article initially published online, the authors omitted acknowledgment recognizing the histology core of the Harvard Stem Cell Institute and several individuals for their assistance. The error has been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

This work was supported jointly by the JDRF and the Leona M. and Harry B. Helmsley Charitable Trust (grant no. 3-SRA-2014-285-M-R (R.L. and D.G.A.)), the US National Institutes of Health (grants EB000244 (R.L.), EB000351 (R.L.), DE013023 (R.L.), CA151884 (R.L.) and UC4DK104218 (D.L.G.)), and through a generous gift from the Tayebati Family Foundation (D.G.A. and R.L.). O.V. was supported by JDRF and Department of Defense Congressionally Directed Medical Research Program (DOD/CDMRP) postdoctoral fellowships (grants 3-2013-178 and W81XWH-13-1-0215, respectively). J.R.M. was supported by a fellowship from the Harvard Stem Cell Institute. J.O. is supported by the Chicago Diabetes Project. The authors acknowledge R. Bogorad for useful discussions and assistance and the Koch Institute Swanson Biotechnology Center for technical support, specifically for the use of the Hope Babette Tang Histology, Microscopy, Flow Cytometry and Animal Imaging and preclinical testing core facilities. We acknowledge the use of imaging resources at the Harvard University Center for Nanoscale Systems, the W.M. Keck Biological Imaging Facility (Whitehead Institute) and the histology core of the Harvard Stem Cell Institute. We would like to thank A. Graham, W. Salmon, C. MacGillivray and J. Wyckoff for their assistance.

Author information

Author notes

    • Arturo J Vegas
    • , Jeffrey R Millman
    •  & Andrew R Bader

    Present addresses: Department of Chemistry, Boston University, Boston, Massachusetts, USA (A.J.V.); Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA (A.R.B.); Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, Missouri, USA (J.R.M.); Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, Missouri, USA (J.R.M.).

    • Arturo J Vegas
    •  & Omid Veiseh

    These authors contributed equally to this work.

Affiliations

  1. David H Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.

    • Arturo J Vegas
    • , Omid Veiseh
    • , Andrew R Bader
    • , Joshua C Doloff
    • , Jie Li
    • , Michael Chen
    • , Karsten Olejnik
    • , Hok Hei Tam
    • , Siddharth Jhunjhunwala
    • , Erin Langan
    • , Stephanie Aresta-Dasilva
    • , Srujan Gandham
    • , Robert Langer
    •  & Daniel G Anderson
  2. Department of Anesthesiology, Boston Children's Hospital, Boston, Massachusetts, USA.

    • Arturo J Vegas
    • , Omid Veiseh
    • , Andrew R Bader
    • , Joshua C Doloff
    • , Jie Li
    • , Michael Chen
    • , Karsten Olejnik
    • , Hok Hei Tam
    • , Siddharth Jhunjhunwala
    • , Erin Langan
    • , Stephanie Aresta-Dasilva
    • , Srujan Gandham
    • , Robert Langer
    •  & Daniel G Anderson
  3. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Omid Veiseh
    • , Hok Hei Tam
    • , Robert Langer
    •  & Daniel G Anderson
  4. Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA.

    • Mads Gürtler
    • , Jeffrey R Millman
    • , Felicia W Pagliuca
    •  & Douglas A Melton
  5. Department of Surgery, Division of Transplantation, University of Illinois at Chicago, Chicago, Illinois, USA.

    • James J McGarrigle
    • , Matthew A Bochenek
    •  & Jose Oberholzer
  6. Section on Islet Cell and Regenerative Biology, Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA.

    • Jennifer Hollister-Lock
    •  & Gordon C Weir
  7. Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

    • Dale L Greiner
  8. Howard Hughes Medical Institute (HHMI), Harvard University, Cambridge, Massachusetts, USA.

    • Douglas A Melton
  9. Division of Health Science Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Robert Langer
    •  & Daniel G Anderson
  10. Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Robert Langer
    •  & Daniel G Anderson

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Contributions

A.J.V., O.V. and D.G.A. designed experiments, analyzed data and wrote the manuscript. M.G., J.R.M., F.W.P. and D.A.M. provided SC-β cells. A.J.V., O.V., M.G., J.R.M., F.W.P., A.R.B., J.C.D., J.L., M.C., K.O., S.J., E.L., S.A.-D., S.G., J.J.M., M.A.B. and J.H.-L. performed experiments. H.H.T. performed statistical analyses of data sets and aided in the preparation of displays communicating data sets. J.O., D.L.G., G.C.W., D.A.M. and R.L. provided conceptual advice and technical support. R.L. and D.G.A. supervised the study. All of the authors discussed the results and assisted in the preparation of the manuscript.

Competing interests

F.W.P., J.R.M., M.G. and D.A.M. declare a financial interest via a patent filed by Harvard University and HHMI on the production of stem cell–derived β-cells. A.J.V., O.V., J.C.D., R.L. and D.G.A. declare financial interests via patents filed by MIT on the material and hydrogel capsule technology.

Corresponding author

Correspondence to Daniel G Anderson.

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DOI

https://doi.org/10.1038/nm.4030

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