title: Concordant but Varied Phenotypes among Duchenne Muscular Dystrophy Patient-Specific Myoblasts Derived using a Human iPSC-Based Model.
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.
authors.affiliation: Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: In Young
authors.initials: IY
authors.lastname: Choi
authors.affiliation: Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: HoTae
authors.initials: H
authors.lastname: Lim
authors.affiliation: 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.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Estrellas
authors.affiliation: 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.
authors.forename: Jyothi
authors.initials: J
authors.lastname: Mula
authors.affiliation: 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.
authors.forename: Tatiana V
authors.initials: TV
authors.lastname: Cohen
authors.affiliation: 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.
authors.forename: Yuanfan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Donnelly
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Richard
authors.affiliation: 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.
authors.forename: Yong Jun
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: 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.
authors.forename: Hyesoo
authors.initials: H
authors.lastname: Kim
authors.affiliation: 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.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kazuki
authors.affiliation: Chromosome Engineering Research Center, Tottori University, Tottori, Japan.
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Oshimura
authors.affiliation: Center for iPS Cell Research and Application, Kyoto University, 606-8501 Kyoto, Japan.
authors.forename: Hongmei Lisa
authors.initials: HL
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Akitsu
authors.initials: A
authors.lastname: Hotta
authors.affiliation: 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.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Rothstein
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Maragakis
authors.affiliation: 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.
authors.forename: Kathryn R
authors.initials: KR
authors.lastname: Wagner
authors.affiliation: 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.
authors.forename: Gabsang
authors.initials: G
authors.lastname: Lee
mesh_terms: D000818:Animals; D002460:Cell Line; D005434:Flow Cytometry; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000473:pathology*; D051379:Mice; D008954:Models, Biological; D024510:Muscle Development; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000473:pathology*; D032446:Myoblasts / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism
chemical_list: D051785:Smad Proteins