title: Maturation of human embryonic stem cell-derived pancreatic progenitors into functional islets capable of treating pre-existing diabetes in mice.
abstract: Diabetes is a chronic debilitating disease that results from insufficient production of insulin from pancreatic β-cells. Islet cell replacement can effectively treat diabetes but is currently severely limited by the reliance upon cadaveric donor tissue. We have developed a protocol to efficiently differentiate commercially available human embryonic stem cells (hESCs) in vitro into a highly enriched PDX1+ pancreatic progenitor cell population that further develops in vivo to mature pancreatic endocrine cells. Immature pancreatic precursor cells were transplanted into immunodeficient mice with streptozotocin-induced diabetes, and glycemia was initially controlled with exogenous insulin. As graft-derived insulin levels increased over time, diabetic mice were weaned from exogenous insulin and human C-peptide secretion was eventually regulated by meal and glucose challenges. Similar differentiation of pancreatic precursor cells was observed after transplant in immunodeficient rats. Throughout the in vivo maturation period hESC-derived endocrine cells exhibited gene and protein expression profiles that were remarkably similar to the developing human fetal pancreas. Our findings support the feasibility of using differentiated hESCs as an alternative to cadaveric islets for treating patients with diabetes.
authors: BetaLogics Venture, Janssen Research and Development, LLC, Raritan, New Jersey, USA. arezani@its.jnj.com
authors: Alireza
authors: A
authors: Rezania
authors: Jennifer E
authors: JE
authors: Bruin
authors: Michael J
authors: MJ
authors: Riedel
authors: Majid
authors: M
authors: Mojibian
authors: Ali
authors: A
authors: Asadi
authors: Jean
authors: J
authors: Xu
authors: Rebecca
authors: R
authors: Gauvin
authors: Kavitha
authors: K
authors: Narayan
authors: Francis
authors: F
authors: Karanu
authors: John J
authors: JJ
authors: O'Neil
authors: Ziliang
authors: Z
authors: Ao
authors: Garth L
authors: GL
authors: Warnock
authors: Timothy J
authors: TJ
authors: Kieffer
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000628:therapy; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000637:transplantation*; D018398:Homeodomain Proteins / Q000096:biosynthesis; D006801:Humans; D007328:Insulin / Q000627:therapeutic use; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism; D008297:Male; D051379:Mice; D010179:Pancreas / Q000166:cytology* / Q000196:embryology; D043484:Proprotein Convertases / Q000096:biosynthesis; D051381:Rats; D013234:Stem Cells / Q000166:cytology; D015534:Trans-Activators / Q000096:biosynthesis
chemical_list: D018398:Homeodomain Proteins; D007328:Insulin; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D043484:Proprotein Convertases