Pathogenic Mutation of ALK2 Inhibits Induced Pluripotent Stem Cell Reprogramming and Maintenance: Mechanisms of Reprogramming and Strategy for Drug Identification§

Authors


  • 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.

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. STEM CELLS2012; 30:2437–2449

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