title: PDGF Facilitates Direct Lineage Reprogramming of Hepatocytes to Functional β-Like Cells Induced by Pdx1 and Ngn3.
abstract: Islet transplantation has been proven to be an effective treatment for patients with type 1 diabetes, but a lack of islet donors limits the use of transplantation therapies. It has been previously demonstrated that hepatocytes can be converted into insulin-producing β-like cells by introducing pancreatic transcription factors, indicating that direct hepatocyte reprogramming holds potential as a treatment for diabetes. However, the efficiency at which functional β-cells can be derived from hepatocyte reprogramming remains low. Here we demonstrated that the combination of Pdx1 and Ngn3 can trigger reprogramming of mouse and human liver cells to insulin-producing cells that exhibit the characteristics of pancreatic β-cells. Treatment with PDGF-AA was found to facilitate Pdx1 and Ngn3-induced reprogramming of hepatocytes to β-like cells with the ability to secrete insulin in response to glucose stimulus. Importantly, this reprogramming strategy could be applied to adult mouse primary hepatocytes, and the transplantation of β-like cells derived from primary hepatocyte reprogramming could ameliorate hyperglycemia in diabetic mice. These findings support the possibility of developing transplantation therapies for type 1 diabetes through the use of β-like cells derived from autologous hepatocyte reprogramming.
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.|Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Fang-Pei
authors.initials: FP
authors.lastname: Chang
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Candy Hsin-Hua
authors.initials: CH
authors.lastname: Cho
authors.affiliation: Department of Medical Biotechnology and Laboratory Science, Chang Gung University, Tao-Yuan, Taiwan.
authors.forename: Chia-Rui
authors.initials: CR
authors.lastname: Shen
authors.affiliation: Institute of Biotechnology, National Taiwan University, Taipei, Taiwan.
authors.forename: Chiao-Yun
authors.initials: CY
authors.lastname: Chien
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Ling-Wen
authors.initials: LW
authors.lastname: Ting
authors.affiliation: Institute of Biotechnology, National Taiwan University, Taipei, Taiwan.
authors.forename: Hsuan-Shu
authors.initials: HS
authors.lastname: Lee
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.|Genomics Research Center, Academia Sinica, Taipei, Taiwan.|Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chia-Ning
authors.initials: CN
authors.lastname: Shen
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D001786:Blood Glucose / Q000032:analysis; D054338:Cell Transdifferentiation / Q000187:drug effects; D002478:Cells, Cultured; D065150:Cellular Reprogramming / Q000187:drug effects*; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000473:pathology / Q000628:therapy; D000077270:Exenatide; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology; D000067757:Glucagon-Like Peptide-1 Receptor / Q000235:genetics / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism / Q000637:transplantation; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014688:Venoms / Q000494:pharmacology
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D001786:Blood Glucose; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose; D018398:Homeodomain Proteins; D007328:Insulin; D009419:Nerve Tissue Proteins; D010455:Peptides; D010982:Platelet-Derived Growth Factor; D020796:Receptor, Platelet-Derived Growth Factor alpha; D015534:Trans-Activators; D014688:Venoms; C407737:Neurog3 protein, mouse; C084010:pancreatic and duodenal homeobox 1 protein; C075278:platelet-derived growth factor A
keywords: Glucagon-like peptide-1 (GLP-1); Hepatocyte transdifferentiation; Lineage reprogramming; Platelet-derived growth factor (PDGF); Type 1 diabetes mellitus; β-Cells