title: Pathogenic mutation of ALK2 inhibits induced pluripotent stem cell reprogramming and maintenance: mechanisms of reprogramming and strategy for drug identification.
abstract: Fibrodysplasia ossificans progressiva (FOP) is a rare congenital disorder characterized by progressive ossification of soft tissues. FOP is caused by mutations in activin receptor-like kinase 2 (ALK2) that cause its constitutive activation and result in dysregulation of BMP signaling. Here, we show that generation of induced pluripotent stem cells (iPSCs) from FOP-derived skin fibroblasts is repressed because of incomplete reprogramming and inhibition of iPSC maintenance. This repression was mostly overcome by specific suppression of ALK2 expression and treatment with an ALK2 inhibitor, indicating that the inhibition of iPSC generation and maintenance observed in FOP-derived skin fibroblasts results from constitutive activation of ALK2. Using this system, we identified an ALK2 inhibitor as a potential candidate for future drug development. This study highlights the potential of the inhibited production and maintenance of iPSCs seen in diseases as a useful phenotype not only for studying the molecular mechanisms underlying iPS reprogramming but also for identifying drug candidates for future therapies.
authors.affiliation: Department of Cell Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University, 2-2-1 Honjo, Kumamoto, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Hamasaki
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Hashizume
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Yamada
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Katayama
authors.forename: Hirohiko
authors.initials: H
authors.lastname: Hohjoh
authors.forename: Noemi
authors.initials: N
authors.lastname: Fusaki
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Nakashima
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Furuya
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Haga
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Takami
authors.forename: Takumi
authors.initials: T
authors.lastname: Era
mesh_terms: D030201:Activin Receptors, Type I / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D018920:Coculture Techniques; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D020125:Mutation, Missense; D009221:Myositis Ossificans / Q000235:genetics / Q000473:pathology*; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction; D012867:Skin / Q000473:pathology; D059467:Transcriptome
chemical_list: C554430:LDN 193189; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C425423:ACVR1 protein, human; D030201:Activin Receptors, Type I