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Long-term glycemic control using polymer-encapsulated human stem cell–derived beta cells in immune-competent mice

Nature Medicine volume 22, pages 306–311 (2016)Cite this article

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A Corrigendum to this article was published on 06 April 2016

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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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Figure 1: SC-β cells encapsulated with TMTD alginate sustain normoglycemia in STZ-treated immune-competent C57BL/6J mice.
Figure 2: SC-β cells encapsulated with TMTD alginate elicit weaker immunological and fibrotic responses in immune-competent C57BL/6J mice.
Figure 3: SC-β cells encapsulated with TMTD alginate sustain long-term normoglycemia in STZ-treated C57BL/6J mice.

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  • 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.

References

  1. Robertson, R.P. Islet transplantation as a treatment for diabetes—a work in progress. N. Engl. J. Med. 350, 694–705 (2004).

    Article  CAS  Google Scholar 

  2. Shapiro, A.M. et al. International trial of the Edmonton protocol for islet transplantation. N. Engl. J. Med. 355, 1318–1330 (2006).

    Article  CAS  Google Scholar 

  3. Hirshberg, B. Lessons learned from the international trial of the Edmonton protocol for islet transplantation. Curr. Diab. Rep. 7, 301–303 (2007).

    Article  Google Scholar 

  4. Pagliuca, F.W. et al. Generation of functional human pancreatic β-cells in vitro. Cell 159, 428–439 (2014).

    Article  CAS  Google Scholar 

  5. Lim, F. & Sun, A.M. Microencapsulated islets as bioartificial endocrine pancreas. Science 210, 908–910 (1980).

    Article  CAS  Google Scholar 

  6. Soon-Shiong, P. et al. Insulin independence in a type 1 diabetic patient after encapsulated islet transplantation. Lancet 343, 950–951 (1994).

    Article  CAS  Google Scholar 

  7. Dolgin, E. Encapsulate this. Nat. Med. 20, 9–11 (2014).

    Article  CAS  Google Scholar 

  8. Shaw, J.E., Sicree, R.A. & Zimmet, P.Z. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res. Clin. Pract. 87, 4–14 (2010).

    Article  CAS  Google Scholar 

  9. Pickup, J.C. Insulin-pump therapy for type 1 diabetes mellitus. N. Engl. J. Med. 366, 1616–1624 (2012).

    Article  CAS  Google Scholar 

  10. Veiseh, O., Tang, B.C., Whitehead, K.A., Anderson, D.G. & Langer, R. Managing diabetes with nanomedicine: challenges and opportunities. Nat. Rev. Drug Discov. 14, 45–57 (2015).

    Article  CAS  Google Scholar 

  11. Shapiro, A.M. et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N. Engl. J. Med. 343, 230–238 (2000).

    Article  CAS  Google Scholar 

  12. Qi, M. et al. Five-year follow-up of patients with type 1 diabetes transplanted with allogeneic islets: the UIC experience. Acta Diabetol. 51, 833–843 (2014).

    Article  CAS  Google Scholar 

  13. Shapiro, A.M. Islet transplantation in type 1 diabetes: ongoing challenges, refined procedures and long-term outcome. Rev. Diabet. Stud. 9, 385–406 (2012).

    Article  Google Scholar 

  14. Vogel, G. Stem cell recipe offers diabetes hope. Science 346, 148 (2014).

    Article  CAS  Google Scholar 

  15. Jacobs-Tulleneers-Thevissen, D. et al. Sustained function of alginate-encapsulated human islet cell implants in the peritoneal cavity of mice leading to a pilot study in a type 1 diabetic patient. Diabetologia 56, 1605–1614 (2013).

    Article  CAS  Google Scholar 

  16. Scharp, D.W. & Marchetti, P. Encapsulated islets for diabetes therapy: history, current progress and critical issues requiring solution. Adv. Drug Deliv. Rev. 67–68, 35–73 (2014).

    Article  Google Scholar 

  17. Lum, Z.P. et al. Prolonged reversal of diabetic state in NOD mice by xenografts of microencapsulated rat islets. Diabetes 40, 1511–1516 (1991).

    Article  CAS  Google Scholar 

  18. Schneider, S. et al. Long-term graft function of adult rat and human islets encapsulated in novel alginate-based microcapsules after transplantation in immunocompetent diabetic mice. Diabetes 54, 687–693 (2005).

    Article  CAS  Google Scholar 

  19. Peppas, N.A., Hilt, J.Z., Khademhosseini, A. & Langer, R. Hydrogels in biology and medicine: from molecular principles to bionanotechnology. Adv. Mater. 18, 1345–1360 (2006).

    Article  CAS  Google Scholar 

  20. Basta, G. et al. Long-term metabolic and immunological follow-up of non-immunosuppressed patients with type 1 diabetes treated with microencapsulated islet allografts: four cases. Diabetes Care 34, 2406–2409 (2011).

    Article  CAS  Google Scholar 

  21. Calafiore, R. et al. Microencapsulated pancreatic islet allografts into non-immunosuppressed patients with type 1 diabetes: first two cases. Diabetes Care 29, 137–138 (2006).

    Article  Google Scholar 

  22. de Groot, M., Schuurs, T.A. & van Schilfgaarde, R. Causes of limited survival of microencapsulated pancreatic islet grafts. J. Surg. Res. 121, 141–150 (2004).

    Article  CAS  Google Scholar 

  23. Tuch, B.E. et al. Safety and viability of microencapsulated human islets transplanted into diabetic humans. Diabetes Care 32, 1887–1889 (2009).

    Article  CAS  Google Scholar 

  24. Elliott, R.B. et al. Intraperitoneal alginate-encapsulated neonatal porcine islets in a placebo-controlled study with 16 diabetic cynomolgus primates. Transplant. Proc. 37, 3505–3508 (2005).

    Article  CAS  Google Scholar 

  25. Omer, A. et al. Survival and maturation of microencapsulated porcine neonatal pancreatic cell clusters transplanted into immunocompetent diabetic mice. Diabetes 52, 69–75 (2003).

    Article  CAS  Google Scholar 

  26. Veiseh, O. et al. Size- and shape-dependent foreign-body immune response to materials implanted in rodents and nonhuman primates. Nat. Mater. 14, 643–651 (2015).

    Article  CAS  Google Scholar 

  27. Vegas, A.J. et al. Combinatorial hydrogel library enables identification of materials that mitigate the foreign-body response in primates. Nat. Biotechnol. doi:10.1038/nbt.3462 (25 January 2016).

  28. Kolb, M. et al. Differences in the fibrogenic response after transfer of active transforming growth factor–β1 gene to lungs of 'fibrosis-prone' and 'fibrosis-resistant' mouse strains. Am. J. Respir. Cell Mol. Biol. 27, 141–150 (2002).

    Article  CAS  Google Scholar 

  29. Dang, T.T. et al. Spatiotemporal effects of a controlled-release anti-inflammatory drug on the cellular dynamics of host response. Biomaterials 32, 4464–4470 (2011).

    Article  CAS  Google Scholar 

  30. King, A., Sandler, S. & Andersson, A. The effect of host factors and capsule composition on the cellular overgrowth on implanted alginate capsules. J. Biomed. Mater. Res. 57, 374–383 (2001).

    Article  CAS  Google Scholar 

  31. Pepper, A.R. et al. A prevascularized subcutaneous device-less site for islet and cellular transplantation. Nat. Biotechnol. 33, 518–523 (2015).

    Article  CAS  Google Scholar 

  32. Lee, S.H. et al. Human beta cell precursors mature into functional insulin-producing cells in an immunoisolation device: implications for diabetes cell therapies. Transplantation 87, 983–991 (2009).

    Article  Google Scholar 

  33. Rezania, A. et al. Maturation of human embryonic stem cell–derived pancreatic progenitors into functional islets capable of treating pre-existing diabetes in mice. Diabetes 61, 2016–2029 (2012).

    Article  CAS  Google Scholar 

  34. Rezania, A. et al. Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells. Nat. Biotechnol. 32, 1121–1133 (2014).

    Article  CAS  Google Scholar 

  35. Wang, T. et al. An encapsulation system for the immunoisolation of pancreatic islets. Nat. Biotechnol. 15, 358–362 (1997).

    Article  CAS  Google Scholar 

Download references

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.

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Author notes

  1. Arturo J Vegas, Jeffrey R Millman & Andrew R Bader

    Present address: 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.).,

  2. Arturo J Vegas and Omid Veiseh: These authors contributed equally to this work.

Authors and 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. Research Division, Section on Islet Cell and Regenerative Biology, 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.

Corresponding author

Correspondence to Daniel G Anderson.

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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.

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Vegas, A., Veiseh, O., Gürtler, M. et al. Long-term glycemic control using polymer-encapsulated human stem cell–derived beta cells in immune-competent mice. Nat Med 22, 306–311 (2016). https://doi.org/10.1038/nm.4030

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