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

IY, Choi  ,  H, Lim  ,  K, Estrellas  ,  J, Mula  ,  TV, Cohen  ,  Y, Zhang  ,  CJ, Donnelly  ,  JP, Richard  ,  YJ, Kim  ,  H, Kim  ,  Y, Kazuki  ,  M, Oshimura  ,  HL, Li  ,  A, Hotta  ,  J, Rothstein  ,  N, Maragakis  ,  KR, Wagner  ,  G, Lee

15 ( 10 )  , pp.2301 - 2312 , 2016-06-07 , Elsevier
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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