Concordant but varied phenotypes among Duchenne muscular dystrophy patient-specific myoblasts derived using a human iPSC-based model | DuchenneXchange

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Scientific Articles

Concordant but varied phenotypes among Duchenne muscular dystrophy patient-specific myoblasts derived using a human iPSC-based model

key information

source: Cell Reports

year: 2016

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

summary/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.

organisation: Johns Hopkins University School of Medicine, USA; Hugo W. Moser Research Institute at Kennedy Krieger, USA; College of Medicine, Kyung Hee University, Korea; Chromosome Engineering Research Center, Tottori University, Japan; Center for iPS Cell Research and Application, Kyoto University, Japan; PRESTO, Japan Science and Technology Agency, Japan

DOI: 10.1016/j.celrep.2016.05.016

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