title: Neural cells play an inhibitory role in pancreatic differentiation of pluripotent stem cells.
abstract: Pancreatic endocrine β-cells derived from embryonic stem (ES) cells and induced pluripotent stem (iPS) cells have received attention as screening systems for therapeutic drugs and as the basis for cell-based therapies. Here, we used a 12-day β-cell differentiation protocol for mouse ES cells and obtained several hit compounds that promoted β-cell differentiation. One of these compounds, mycophenolic acid (MPA), effectively promoted ES cell differentiation with a concomitant reduction of neuronal cells. The existence of neural cell-derived inhibitory humoral factors for β-cell differentiation was suggested using a co-culture system. Based on gene array analysis, we focused on the Wnt/β-catenin pathway and showed that the Wnt pathway inhibitor reversed MPA-induced β-cell differentiation. Wnt pathway activation promoted β-cell differentiation also in human iPS cells. Our results showed that Wnt signaling activation positively regulates β-cell differentiation, and represent a downstream target of the neural inhibitory factor.
authors.affiliation: Division of Stem Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Honjo 2-2-1, Kumamoto, 860-0811, Japan.
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Nakashima
authors.affiliation: Division of Stem Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Honjo 2-2-1, Kumamoto, 860-0811, Japan.
authors.forename: Mayu
authors.initials: M
authors.lastname: Morooka
authors.affiliation: Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259-B-25 Nagatsuta-cho, Midori-ku, Yokohama, 226-8501, Japan.
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Shiraki
authors.affiliation: Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259-B-25 Nagatsuta-cho, Midori-ku, Yokohama, 226-8501, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Sakano
authors.affiliation: Division of Stem Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Honjo 2-2-1, Kumamoto, 860-0811, Japan.|Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259-B-25 Nagatsuta-cho, Midori-ku, Yokohama, 226-8501, Japan.
authors.forename: Soichiro
authors.initials: S
authors.lastname: Ogaki
authors.affiliation: Department of Neuropharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe Street, Mizuho, Nagoya, 467-8603, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Kume
authors.affiliation: Division of Stem Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Honjo 2-2-1, Kumamoto, 860-0811, Japan.|Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259-B-25 Nagatsuta-cho, Midori-ku, Yokohama, 226-8501, Japan.|Program for Leading Graduate Schools, Health life science: Interdisciplinary and Glocal Oriented (HIGO), Kumamoto University, Honjo 2-2-1, Kumamoto, 860-0811, Japan.
authors.forename: Shoen
authors.initials: S
authors.lastname: Kume
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D018920:Coculture Techniques; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology*; D051379:Mice; D009173:Mycophenolic Acid / Q000494:pharmacology; D009474:Neurons / Q000166:cytology*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D039904:Pluripotent Stem Cells / Q000166:cytology*; D060449:Wnt Signaling Pathway / Q000187:drug effects
chemical_list: D009173:Mycophenolic Acid