Pathogenic mutation of ALK2 inhibits induced pluripotent stem cell reprogramming and maintenance

Mechanisms of reprogramming and strategy for drug identification

Makoto Hamasaki, Yoshinobu Hashizume, Yoshinori Yamada, Tomohiko Katayama, Hirohiko Hohjoh, Noemi Fusaki, Yasuharu Nakashima, Hirokazu Furuya, Nobuhiko Haga, Yoichiro Takami, Takumi Era

Research output: Contribution to journalArticle

43 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2437-2449
Number of pages13
JournalSTEM CELLS
Volume30
Issue number11
DOIs
Publication statusPublished - Nov 1 2012

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Activin Receptors
Induced Pluripotent Stem Cells
Myositis Ossificans
Maintenance
Mutation
Pharmaceutical Preparations
Fibroblasts
Congenital, Hereditary, and Neonatal Diseases and Abnormalities
Skin
Osteogenesis
Cellular Reprogramming
Phenotype

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Developmental Biology
  • Cell Biology

Cite this

Pathogenic mutation of ALK2 inhibits induced pluripotent stem cell reprogramming and maintenance : Mechanisms of reprogramming and strategy for drug identification. / Hamasaki, Makoto; Hashizume, Yoshinobu; Yamada, Yoshinori; Katayama, Tomohiko; Hohjoh, Hirohiko; Fusaki, Noemi; Nakashima, Yasuharu; Furuya, Hirokazu; Haga, Nobuhiko; Takami, Yoichiro; Era, Takumi.

In: STEM CELLS, Vol. 30, No. 11, 01.11.2012, p. 2437-2449.

Research output: Contribution to journalArticle

Hamasaki, M, Hashizume, Y, Yamada, Y, Katayama, T, Hohjoh, H, Fusaki, N, Nakashima, Y, Furuya, H, Haga, N, Takami, Y & Era, T 2012, 'Pathogenic mutation of ALK2 inhibits induced pluripotent stem cell reprogramming and maintenance: Mechanisms of reprogramming and strategy for drug identification', STEM CELLS, vol. 30, no. 11, pp. 2437-2449. https://doi.org/10.1002/stem.1221
Hamasaki, Makoto ; Hashizume, Yoshinobu ; Yamada, Yoshinori ; Katayama, Tomohiko ; Hohjoh, Hirohiko ; Fusaki, Noemi ; Nakashima, Yasuharu ; Furuya, Hirokazu ; Haga, Nobuhiko ; Takami, Yoichiro ; Era, Takumi. / Pathogenic mutation of ALK2 inhibits induced pluripotent stem cell reprogramming and maintenance : Mechanisms of reprogramming and strategy for drug identification. In: STEM CELLS. 2012 ; Vol. 30, No. 11. pp. 2437-2449.
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