Open AccessAn inhibitor of fibroblast growth factor receptor-1 (FGFR1) promotes late-stage terminal differentiation from NGN3+ pancreatic endocrine progenitors
Author(s) -
Yzumi YamashitaSugahara,
Masahito Matsumoto,
Manami Ohtaka,
Ken Nishimura,
Mahito Nakanishi,
Kohnosuke Mitani,
Yasushi Okazaki
Publication year - 2016
Publication title -
scientific reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.24
H-Index - 213
ISSN - 2045-2322
DOI - 10.1038/srep35908
Subject(s) - fibroblast growth factor receptor 1 , fibroblast growth factor , progenitor cell , endocrine system , terminal (telecommunication) , microbiology and biotechnology , enteroendocrine cell , receptor , biology , endocrinology , cancer research , medicine , chemistry , stem cell , computer science , hormone , biochemistry , telecommunications
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 h iPSCs ( I NS - Ve nus/ N GN3 -mCher ry ) (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.