2. Academic Validation
  3. Concordant but Varied Phenotypes among Duchenne Muscular Dystrophy Patient-Specific Myoblasts Derived using a Human iPSC-Based Model

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

  • Cell Rep. 2016 Jun 7;15(10):2301-2312. doi: 10.1016/j.celrep.2016.05.016.
In Young Choi 1,  HoTae Lim 1,  Kenneth Estrellas 2,  Jyothi Mula 3,  Tatiana V Cohen 3,  Yuanfan Zhang 2,  Christopher J Donnelly 4,  Jean-Philippe Richard 5,  Yong Jun Kim 6,  Hyesoo Kim 7,  Yasuhiro Kazuki 8,  Mitsuo Oshimura 9,  Hongmei Lisa Li 10,  Akitsu Hotta 11,  Jeffrey Rothstein 12,  Nicholas Maragakis 5,  Kathryn R Wagner 13,  Gabsang Lee 14
Affiliations

Affiliations

  • 1 Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • 2 Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, MD 21205, USA.
  • 3 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, MD 21205, USA.
  • 4 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • 5 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • 6 Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pathology, College of Medicine, Kyung Hee University, 02447 Seoul, Korea.
  • 7 Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Stem Cell Core Facility, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • 8 Chromosome Engineering Research Center, Tottori University, Tottori, Japan; Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori University, 680-0805 Tottori, Japan.
  • 9 Chromosome Engineering Research Center, Tottori University, Tottori, Japan.
  • 10 Center for iPS Cell Research and Application, Kyoto University, 606-8501 Kyoto, Japan.
  • 11 Center for iPS Cell Research and Application, Kyoto University, 606-8501 Kyoto, Japan; iCeMS, Kyoto University, 606-8501 Kyoto, Japan; PRESTO, Japan Science and Technology Agency, 332-0012 Kawaguchi, Japan.
  • 12 Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • 13 Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, MD 21205, USA. Electronic address: wagnerk@kennedykrieger.org.
  • 14 Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: glee48@jhmi.edu.
PMID: 27239027 DOI: 10.1016/j.celrep.2016.05.016
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.

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