title: An inhibitor of fibroblast growth factor receptor-1 (FGFR1) promotes late-stage terminal differentiation from NGN3+ pancreatic endocrine progenitors.
abstract: Human induced pluripotent stem cells (hiPSCs) provide a potential resource for regenerative medicine. To identify the signalling pathway(s) contributing to the development of functional β cells, we established a tracing model consisting of dual knock-in hiPSCs (INS-Venus/NGN3-mCherry) (hIveNry) expressing the fluorescent proteins Venus and mCherry under the control of intrinsic insulin (INS) and neurogenin 3 (NGN3) promoters, respectively. hIveNry iPSCs differentiated into NGN3- and mCherry-positive endocrine progenitors and then into Venus-positive β cells expressing INS, PDX1, NKX6.1, and glucokinase (GCK). Using these cells, we conducted high-throughput screening of chemicals and identified a specific kinase inhibitor of fibroblast growth factor receptor 1 (FGFR1) that acted in a stage-dependent manner to promote the terminal differentiation of pancreatic endocrine cells, including β cells, from the intermediate stage of pancreatic endocrine progenitors while blocking the early development of pancreatic progenitors. This FGFR1 inhibitor augmented the expression of functional β cell markers (SLC30A8 and ABCC8) and improved glucose-stimulated INS secretion. Our findings indicate that the hIveNry model could provide further insights into the mechanisms of hiPS-derived β cell differentiation controlled by FGFR1-mediated regulatory pathways in a temporal-dependent fashion.
authors: Division of Functional Genomics and Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan.
authors: Yzumi
authors: Y
authors: Yamashita-Sugahara
authors: Division of Functional Genomics and Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan.
authors: Masahito
authors: M
authors: Matsumoto
authors: Biotechnology Research Institute for Drug Discovery, National Institute of Advanced Industrial Science and Technology (AIST), Ibaraki, Japan.
authors: Manami
authors: M
authors: Ohtaka
authors: Laboratory of Gene Regulation, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan.
authors: Ken
authors: K
authors: Nishimura
authors: Biotechnology Research Institute for Drug Discovery, National Institute of Advanced Industrial Science and Technology (AIST), Ibaraki, Japan.
authors: Mahito
authors: M
authors: Nakanishi
authors: Division of Gene Therapy, Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan.
authors: Kohnosuke
authors: K
authors: Mitani
authors: Division of Functional Genomics and Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan.
authors: Yasushi
authors: Y
authors: Okazaki
mesh_terms: D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D019070:Cell Lineage; D055879:Gene Knock-In Techniques; D018390:Gene Targeting; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D000097573:Red Fluorescent Protein
chemical_list: D001426:Bacterial Proteins; D051792:Basic Helix-Loop-Helix Proteins; D007328:Insulin; D008164:Luminescent Proteins; D009419:Nerve Tissue Proteins; D051496:Receptor, Fibroblast Growth Factor, Type 1; D000097573:Red Fluorescent Protein; C498695:NEUROG3 protein, human; C054562:yellow fluorescent protein, Bacteria; C496348:FGFR1 protein, human