title: Long-term glycemic control using polymer-encapsulated human stem cell-derived beta cells in immune-competent mice.
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.
authors.affiliation: David H Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.|Department of Anesthesiology, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Arturo J
authors.initials: AJ
authors.lastname: Vegas
authors.affiliation: David H Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.|Department of Anesthesiology, Boston Children's Hospital, Boston, Massachusetts, USA.|Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Omid
authors.initials: O
authors.lastname: Veiseh
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Mads
authors.initials: M
authors.lastname: Gürtler
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Millman
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Felicia W
authors.initials: FW
authors.lastname: Pagliuca
authors.affiliation: David H Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.|Department of Anesthesiology, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Bader
authors.affiliation: David H Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.|Department of Anesthesiology, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Doloff
authors.affiliation: David H Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.|Department of Anesthesiology, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: David H Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.|Department of Anesthesiology, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Michael
authors.identifier: http://orcid.org/0000-0002-1590-768X
authors.initials: M
authors.lastname: Chen
authors.affiliation: David H Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.|Department of Anesthesiology, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Karsten
authors.initials: K
authors.lastname: Olejnik
authors.affiliation: David H Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.|Department of Anesthesiology, Boston Children's Hospital, Boston, Massachusetts, USA.|Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Hok Hei
authors.initials: HH
authors.lastname: Tam
authors.affiliation: David H Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.|Department of Anesthesiology, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Siddharth
authors.initials: S
authors.lastname: Jhunjhunwala
authors.affiliation: David H Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.|Department of Anesthesiology, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: Langan
authors.affiliation: David H Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.|Department of Anesthesiology, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Aresta-Dasilva
authors.affiliation: David H Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.|Department of Anesthesiology, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Srujan
authors.initials: S
authors.lastname: Gandham
authors.affiliation: Department of Surgery, Division of Transplantation, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: McGarrigle
authors.affiliation: Department of Surgery, Division of Transplantation, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Bochenek
authors.affiliation: Section on Islet Cell and Regenerative Biology, Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hollister-Lock
authors.affiliation: Department of Surgery, Division of Transplantation, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Jose
authors.initials: J
authors.lastname: Oberholzer
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Dale L
authors.initials: DL
authors.lastname: Greiner
authors.affiliation: Section on Islet Cell and Regenerative Biology, Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA.
authors.forename: Gordon C
authors.initials: GC
authors.lastname: Weir
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA.|Howard Hughes Medical Institute (HHMI), Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Melton
authors.affiliation: David H Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.|Department of Anesthesiology, Boston Children's Hospital, Boston, Massachusetts, USA.|Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Division of Health Science Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Langer
authors.affiliation: David H Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.|Department of Anesthesiology, Boston Children's Hospital, Boston, Massachusetts, USA.|Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Division of Health Science Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Anderson
mesh_terms: D000464:Alginates; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D015153:Blotting, Western; D002096:C-Peptide / Q000378:metabolism*; D018929:Cell Culture Techniques; D002454:Cell Differentiation; D017690:Cell Transplantation / Q000379:methods*; D002853:Chromatography, Liquid; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000628:therapy*; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism / Q000628:therapy*; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells / Q000166:cytology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005549:Foreign-Body Reaction / Q000517:prevention & control*; D006801:Humans; D020100:Hydrogels; D007121:Immunocompetence; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism / Q000637:transplantation*; D051379:Mice; D018613:Microscopy, Confocal; D008858:Microscopy, Phase-Contrast; D009025:Morpholines; D011108:Polymers; D053719:Tandem Mass Spectrometry; D014230:Triazoles
chemical_list: D000464:Alginates; D001786:Blood Glucose; D002096:C-Peptide; D020100:Hydrogels; D007328:Insulin; D009025:Morpholines; D011108:Polymers; D014230:Triazoles; C028971:thiamorpholine