Concordant but Varied Phenotypes among Duchenne Muscular Dystrophy Patient-Specific Myoblasts Derived using a Human iPSC-Based Model

In Young Choi, Ho Tae Lim, Kenneth Estrellas, Jyothi Mula, Tatiana V. Cohen, Yuanfan Zhang, Christopher J. Donnelly, Jean Philippe Richard, Yong Jun Kim, Hyesoo Kim, Yasuhiro Kazuki, Mitsuo Oshimura, Hongmei Lisa Li, Akitsu Hotta, Jeffrey Rothstein, Nicholas Maragakis, Kathryn R. Wagner, Gabsang Lee

Research output: Contribution to journalArticle

Abstract

Duchenne muscular dystrophy (DMD) remains an intractable genetic disease. Althogh there are several animal models of DMD, there is no human cell model that carries patient-specific DYSTROPHIN mutations. Here, we present a human DMD model using human induced pluripotent stem cells (hiPSCs). Our model reveals concordant disease-related phenotypes with patient-dependent variation, which are partially reversed by genetic and pharmacological approaches. Our "chemical-compound-based" strategy successfully directs hiPSCs into expandable myoblasts, which exhibit a myogenic transcriptional program, forming striated contractile myofibers and participating in muscle regeneration in vivo. DMD-hiPSC-derived myoblasts show disease-related phenotypes with patient-to-patient variability, including aberrant expression of inflammation or immune-response genes and collagens, increased BMP/TGFβ signaling, and reduced fusion competence. Furthermore, by genetic correction and pharmacological "dual-SMAD" inhibition, the DMD-hiPSC-derived myoblasts and genetically corrected isogenic myoblasts form "rescued" multi-nucleated myotubes. In conclusion, our findings demonstrate the feasibility of establishing a human "DMD-in-a-dish" model using hiPSC-based disease modeling.

Original languageEnglish (US)
Pages (from-to)2301-2312
Number of pages12
JournalCell Reports
Volume15
Issue number10
DOIs
StatePublished - Jun 7 2016

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Choi, I. Y., Lim, H. T., Estrellas, K., Mula, J., Cohen, T. V., Zhang, Y., Donnelly, C. J., Richard, J. P., Kim, Y. J., Kim, H., Kazuki, Y., Oshimura, M., Li, H. L., Hotta, A., Rothstein, J., Maragakis, N., Wagner, K. R., & Lee, G. (2016). Concordant but Varied Phenotypes among Duchenne Muscular Dystrophy Patient-Specific Myoblasts Derived using a Human iPSC-Based Model. Cell Reports, 15(10), 2301-2312. https://doi.org/10.1016/j.celrep.2016.05.016