title: BMP-SMAD-ID promotes reprogramming to pluripotency by inhibiting p16/INK4A-dependent senescence.
abstract: Fibrodysplasia ossificans progressiva (FOP) patients carry a missense mutation in ACVR1 [617G > A (R206H)] that leads to hyperactivation of BMP-SMAD signaling. Contrary to a previous study, here we show that FOP fibroblasts showed an increased efficiency of induced pluripotent stem cell (iPSC) generation. This positive effect was attenuated by inhibitors of BMP-SMAD signaling (Dorsomorphin or LDN1931890) or transducing inhibitory SMADs (SMAD6 or SMAD7). In normal fibroblasts, the efficiency of iPSC generation was enhanced by transducing mutant ACVR1 (617G > A) or SMAD1 or adding BMP4 protein at early times during the reprogramming. In contrast, adding BMP4 at later times decreased iPSC generation. ID genes, transcriptional targets of BMP-SMAD signaling, were critical for iPSC generation. The BMP-SMAD-ID signaling axis suppressed p16/INK4A-mediated cell senescence, a major barrier to reprogramming. These results using patient cells carrying the ACVR1 R206H mutation reveal how cellular signaling and gene expression change during the reprogramming processes.
authors: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158; yamanaka@cira.kyoto-u.ac.jp yohei.hayashi@md.tsukuba.ac.jp.|Laboratory of Gene Regulation, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan.
authors: Yohei
authors: Y
authors: Hayashi
authors: Department of Medicine and the Institute for Human Genetics, University of California, San Francisco, CA 94143.
authors: Edward C
authors: EC
authors: Hsiao
authors: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158.
authors: Salma
authors: S
authors: Sami
authors: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158.
authors: Mariselle
authors: M
authors: Lancero
authors: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158.|Developmental Biology and Regenerative Medicine Program, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA 90027.|Department of Surgery, Division of Pediatric Surgery, Children's Hospital Los Angeles, Los Angeles, CA 90027.
authors: Christopher R
authors: CR
authors: Schlieve
authors: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158.
authors: Trieu
authors: T
authors: Nguyen
authors: Department of Fundamental Cell Technology, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.
authors: Koyori
authors: K
authors: Yano
authors: Department of Fundamental Cell Technology, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.
authors: Ayako
authors: A
authors: Nagahashi
authors: Department of Life Sciences Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.
authors: Makoto
authors: M
authors: Ikeya
authors: Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.|Department of Tissue Regeneration, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.|Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan.
authors: Yoshihisa
authors: Y
authors: Matsumoto
authors: Laboratory of Gene Regulation, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan.
authors: Ken
authors: K
authors: Nishimura
authors: Laboratory of Gene Regulation, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan.
authors: Aya
authors: A
authors: Fukuda
authors: Laboratory of Gene Regulation, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan.
authors: Koji
authors: K
authors: Hisatake
authors: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158.
authors: Kiichiro
authors: K
authors: Tomoda
authors: Department of Fundamental Cell Technology, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.
authors: Isao
authors: I
authors: Asaka
authors: Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.|Department of Tissue Regeneration, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.|Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
authors: Junya
authors: J
authors: Toguchida
authors: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158.|Department of Medicine and the Institute for Human Genetics, University of California, San Francisco, CA 94143.|Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143.
authors: Bruce R
authors: BR
authors: Conklin
authors: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158; yamanaka@cira.kyoto-u.ac.jp yohei.hayashi@md.tsukuba.ac.jp.|Department of Life Sciences Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.
authors: Shinya
authors: S
authors: Yamanaka
mesh_terms: D030201:Activin Receptors, Type I / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002460:Cell Line; D065150:Cellular Reprogramming; D016922:Cellular Senescence; D002648:Child; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism*; D008297:Male; D008822:Mice, Transgenic; D008875:Middle Aged; D009154:Mutation; D009221:Myositis Ossificans / Q000235:genetics; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism*
chemical_list: D019485:Bone Morphogenetic Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D051785:Smad Proteins; C425423:ACVR1 protein, human; D030201:Activin Receptors, Type I
keywords: BMP; FOP; pluripotency; reprogramming; senescence