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
  • 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: [email protected].
  • 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: [email protected].
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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