title: Differentiation and transplantation of functional pancreatic beta cells generated from induced pluripotent stem cells derived from a type 1 diabetes mouse model.
abstract: The nonobese diabetic (NOD) mouse is a classical animal model for autoimmune type 1 diabetes (T1D), closely mimicking features of human T1D. Thus, the NOD mouse presents an opportunity to test the effectiveness of induced pluripotent stem cells (iPSCs) as a therapeutic modality for T1D. Here, we demonstrate a proof of concept for cellular therapy using NOD mouse-derived iPSCs (NOD-iPSCs). We generated iPSCs from NOD mouse embryonic fibroblasts or NOD mouse pancreas-derived epithelial cells (NPEs), and applied directed differentiation protocols to differentiate the NOD-iPSCs toward functional pancreatic beta cells. Finally, we investigated whether the NPE-iPSC-derived insulin-producing cells could normalize hyperglycemia in transplanted diabetic mice. The NOD-iPSCs showed typical embryonic stem cell-like characteristics such as expression of markers for pluripotency, in vitro differentiation, teratoma formation, and generation of chimeric mice. We developed a method for stepwise differentiation of NOD-iPSCs into insulin-producing cells, and found that NPE-iPSCs differentiate more readily into insulin-producing cells. The differentiated NPE-iPSCs expressed diverse pancreatic beta cell markers and released insulin in response to glucose and KCl stimulation. Transplantation of the differentiated NPE-iPSCs into diabetic mice resulted in kidney engraftment. The engrafted cells responded to glucose by secreting insulin, thereby normalizing blood glucose levels. We propose that NOD-iPSCs will provide a useful tool for investigating genetic susceptibility to autoimmune diseases and generating a cellular interaction model of T1D, paving the way for the potential application of patient-derived iPSCs in autologous beta cell transplantation for treating diabetes.
authors.affiliation: 1 Department of Animal Biotechnology (BK21), Animal Resources Research Center, and SMART-IABS,  Konkuk University , Seoul, Republic of Korea.
authors.forename: Kilsoo
authors.initials: K
authors.lastname: Jeon
authors.forename: Hyejin
authors.initials: H
authors.lastname: Lim
authors.forename: Jung-Hyun
authors.initials: JH
authors.lastname: Kim
authors.forename: Nguyen Van
authors.initials: NV
authors.lastname: Thuan
authors.forename: Seung Hwa
authors.initials: SH
authors.lastname: Park
authors.forename: Yu-Mi
authors.initials: YM
authors.lastname: Lim
authors.forename: Hye-Yeon
authors.initials: HY
authors.lastname: Choi
authors.forename: Eung-Ryoung
authors.initials: ER
authors.lastname: Lee
authors.forename: Jin-Hoi
authors.initials: JH
authors.lastname: Kim
authors.forename: Myung-Shik
authors.initials: MS
authors.lastname: Lee
authors.forename: Ssang-Goo
authors.initials: SG
authors.lastname: Cho
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001786:Blood Glucose; D002454:Cell Differentiation; D002678:Chimera / Q000235:genetics / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000628:therapy*; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D020869:Gene Expression Profiling; D005855:Germ Layers / Q000166:cytology / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D006943:Hyperglycemia / Q000628:therapy; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000637:transplantation*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011189:Potassium Chloride / Q000494:pharmacology; D013311:Streptozocin; D013724:Teratoma / Q000378:metabolism
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D007328:Insulin; D013311:Streptozocin; D011189:Potassium Chloride; D005947:Glucose