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Embryonic Stem Cells/Induced Pluripotent Stem Cells
Article first published online: 22 OCT 2012
Copyright © 2012 AlphaMed Press
Volume 30, Issue 11, pages 2437–2449, November 2012
How to Cite
Hamasaki, M., Hashizume, Y., Yamada, Y., Katayama, T., Hohjoh, H., Fusaki, N., Nakashima, Y., Furuya, H., Haga, N., Takami, Y. and 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, 30: 2437–2449. doi: 10.1002/stem.1221
Author contributions: T.E.: designed all experiments and edited the manuscript; M.H., Y.Y., Y.T., and T.K.: performed the experiments, analyzed data, and edited the manuscript; Y.H.: designed and performed part of the drug candidate experiments and edited the manuscript; N.F.: produced and provided Sendai virus vectors and edited the manuscript; H.H.: designed and performed part of the shRNA experiments and edited the manuscript; Y.N., H.F., and N.H.: provided the patient samples and data and edited the manuscript; T.E and Y.T.: wrote and prepared the manuscript and edited the manuscript.
Disclosure of potential conflicts of interest is found at the end of this article.
First published online in STEM CELLSEXPRESS August 7, 2012.
- Issue published online: 22 OCT 2012
- Article first published online: 22 OCT 2012
- Accepted manuscript online: 4 SEP 2012 10:01AM EST
- Manuscript Accepted: 3 AUG 2012
- Manuscript Received: 23 MAR 2012
- Ministry of Health, Labor, and Welfare of Japan and Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency
- Induced pluripotent stem cells;
- Experimental models
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. STEM CELLS2012; 30:2437–2449