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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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.
Supplementary Figures 1–7
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Alginate encapsulation as long-term immune protection of allogeneic pancreatic islet cells transplanted into the omental bursa of macaques
Nature Biomedical Engineering (2018)