title: Maturation and function of human embryonic stem cell-derived pancreatic progenitors in macroencapsulation devices following transplant into mice.
abstract: OBJECTIVE
  Islet transplantation is a promising cell therapy for patients with diabetes, but it is currently limited by the reliance upon cadaveric donor tissue. We previously demonstrated that human embryonic stem cell (hESC)-derived pancreatic progenitor cells matured under the kidney capsule in a mouse model of diabetes into glucose-responsive insulin-secreting cells capable of reversing diabetes. However, the formation of cells resembling bone and cartilage was a major limitation of that study. Therefore, we developed an improved differentiation protocol that aimed to prevent the formation of off-target mesoderm tissue following transplantation. We also examined how variation within the complex host environment influenced the development of pancreatic progenitors in vivo.
  
  
  METHODS
  The hESCs were differentiated for 14 days into pancreatic progenitor cells and transplanted either under the kidney capsule or within Theracyte (TheraCyte, Laguna Hills, CA, USA) devices into diabetic mice.
  
  
  RESULTS
  Our revised differentiation protocol successfully eliminated the formation of non-endodermal cell populations in 99% of transplanted mice and generated grafts containing >80% endocrine cells. Progenitor cells developed efficiently into pancreatic endocrine tissue within macroencapsulation devices, despite lacking direct contact with the host environment, and reversed diabetes within 3 months. The preparation of cell aggregates pre-transplant was critical for the formation of insulin-producing cells in vivo and endocrine cell development was accelerated within a diabetic host environment compared with healthy mice. Neither insulin nor exendin-4 therapy post-transplant affected the maturation of macroencapsulated cells.
  
  
  CONCLUSIONS
  Efficient differentiation of hESC-derived pancreatic endocrine cells can occur in a macroencapsulation device, yielding glucose-responsive insulin-producing cells capable of reversing diabetes.
authors.affiliation: Laboratory of Molecular and Cellular Medicine, Department of Cellular & Physiological Sciences, Life Sciences Institute, University of British Columbia, Room 5308-2350 Health Sciences Mall, Vancouver, BC, Canada V6T 1Z3.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Bruin
authors.forename: Alireza
authors.initials: A
authors.lastname: Rezania
authors.forename: Jean
authors.initials: J
authors.lastname: Xu
authors.forename: Kavitha
authors.initials: K
authors.lastname: Narayan
authors.forename: Jessica K
authors.initials: JK
authors.lastname: Fox
authors.forename: John J
authors.initials: JJ
authors.lastname: O'Neil
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Kieffer
mesh_terms: D000818:Animals; D002460:Cell Line; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000637:transplantation; D000077270:Exenatide; D006801:Humans; D007150:Immunohistochemistry; D050417:Insulin-Secreting Cells / Q000166:cytology*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D010179:Pancreas / Q000166:cytology*; D010455:Peptides / Q000494:pharmacology; D013234:Stem Cells / Q000166:cytology*; D014688:Venoms / Q000494:pharmacology
chemical_list: D010455:Peptides; D014688:Venoms; D000077270:Exenatide