title: Generation of functional insulin-producing cells from neonatal porcine liver-derived cells by PDX1/VP16, BETA2/NeuroD and MafA.
abstract: Surrogate β-cells derived from stem cells are needed to cure type 1 diabetes, and neonatal liver cells may be an attractive alternative to stem cells for the generation of β-cells. In this study, we attempted to generate insulin-producing cells from neonatal porcine liver-derived cells using adenoviruses carrying three genes: pancreatic and duodenal homeobox factor1 (PDX1)/VP16, BETA2/NeuroD and v-maf musculo aponeurotic fibrosarcoma oncogene homolog A (MafA), which are all known to play critical roles in pancreatic development. Isolated neonatal porcine liver-derived cells were sequentially transduced with triple adenoviruses and grown in induction medium containing a high concentration of glucose, epidermal growth factors, nicotinamide and a low concentration of serum following the induction of aggregation for further maturation. We noted that the cells displayed a number of molecular characteristics of pancreatic β-cells, including expressing several transcription factors necessary for β-cell development and function. In addition, these cells synthesized and physiologically secreted insulin. Transplanting these differentiated cells into streptozotocin-induced immunodeficient diabetic mice led to the reversal of hyperglycemia, and more than 18% of the cells in the grafts expressed insulin at 6 weeks after transplantation. These data suggested that neonatal porcine liver-derived cells can be differentiated into functional insulin-producing cells under the culture conditions presented in this report and indicated that neonatal porcine liver-derived cells (NPLCs) might be useful as a potential source of cells for β-cell replacement therapy in efforts to cure type I diabetes.
authors.affiliation: Department of Endocrinology and Metabolism, College of Medicine, The Catholic University of Korea, Seoul, Korea ; Seoul St. Mary's Hospital Convergent Research Consortium for Immunologic Disease, Seoul, Korea.
authors.forename: Dong-Sik
authors.initials: DS
authors.lastname: Ham
authors.forename: Juyoung
authors.initials: J
authors.lastname: Shin
authors.forename: Ji-Won
authors.initials: JW
authors.lastname: Kim
authors.forename: Heon-Seok
authors.initials: HS
authors.lastname: Park
authors.forename: Jae-Hyoung
authors.initials: JH
authors.lastname: Cho
authors.forename: Kun-Ho
authors.initials: KH
authors.lastname: Yoon
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis* / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism; D005947:Glucose / Q000235:genetics / Q000378:metabolism; D064593:Heterografts; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000637:transplantation*; D008099:Liver; D051473:Maf Transcription Factors, Large / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D013552:Swine; D015534:Trans-Activators / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004815:Epidermal Growth Factor; D005947:Glucose; D007328:Insulin; D051473:Maf Transcription Factors, Large; D015534:Trans-Activators