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

Arturo J. Vegas, Omid Veiseh, Mads Gürtler, Jeffrey R. Millman, Felicia W. Pagliuca, Andrew R. Bader, Joshua C. Doloff, Jie Li, Michael Chen, Karsten Olejnik, Hok Hei Tam, Siddharth Jhunjhunwala, Erin Langan, Stephanie Aresta-Dasilva, Srujan Gandham, James J. McGarrigle, Matthew A. Bochenek, Jennifer Hollister-Lock, Jose Oberholzer, Dale L. GreinerGordon C. Weir, Douglas A. Melton, Robert Langer, Daniel G. Anderson

Research output: Contribution to journalArticle

292 Scopus citations

Abstract

The transplantation of glucose-responsive, insulin-producing cells offers the potential for restoring glycemic control in individuals with diabetes. Pancreas transplantation and the infusion of cadaveric islets are currently implemented clinically, but these approaches are limited by the adverse effects of immunosuppressive therapy over the lifetime of the recipient and the limited supply of donor tissue. 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 therapy. Strategies to address the immunosuppression concerns include immunoisolation of insulin-producing cells with porous biomaterials that function as an immune barrier. However, clinical implementation has been challenging because of host immune responses to the implant materials. 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.

Original languageEnglish
Pages (from-to)306-311
Number of pages6
JournalNature medicine
Volume22
Issue number3
DOIs
StatePublished - Mar 1 2016

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    Vegas, A. J., Veiseh, O., Gürtler, M., Millman, J. R., Pagliuca, F. W., Bader, A. R., Doloff, J. C., Li, J., Chen, M., Olejnik, K., Tam, H. H., Jhunjhunwala, S., Langan, E., Aresta-Dasilva, S., Gandham, S., McGarrigle, J. J., Bochenek, M. A., Hollister-Lock, J., Oberholzer, J., ... Anderson, D. G. (2016). Long-term glycemic control using polymer-encapsulated human stem cell-derived beta cells in immune-competent mice. Nature medicine, 22(3), 306-311. https://doi.org/10.1038/nm.4030