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

In Young Choi; HoTae 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

doi:10.1016/j.celrep.2016.05.016

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. Epub 2016 May 26.

Authors

In Young Choi¹, HoTae Lim¹, Kenneth Estrellas², Jyothi Mula³, Tatiana V Cohen³, Yuanfan Zhang², Christopher J Donnelly⁴, Jean-Philippe Richard⁵, Yong Jun Kim⁶, Hyesoo Kim⁷, Yasuhiro Kazuki⁸, Mitsuo Oshimura⁹, Hongmei Lisa Li¹⁰, Akitsu Hotta¹¹, Jeffrey Rothstein¹², Nicholas Maragakis⁵, Kathryn R Wagner¹³, Gabsang Lee¹⁴

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line
Flow Cytometry
Humans
Induced Pluripotent Stem Cells / pathology*
Mice
Models, Biological*
Muscle Development
Muscle Fibers, Skeletal / metabolism
Muscular Dystrophy, Duchenne / genetics
Muscular Dystrophy, Duchenne / pathology*
Myoblasts / metabolism
Myoblasts / pathology*
Phenotype
Signal Transduction
Smad Proteins / metabolism

Substances

Smad Proteins