Format

Send to

Choose Destination
Cell Rep. 2016 Jun 7;15(10):2301-2312. doi: 10.1016/j.celrep.2016.05.016. Epub 2016 May 26.

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

Author information

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.

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.

PMID:
27239027
DOI:
10.1016/j.celrep.2016.05.016
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center