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

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. DMDhiPSC-derived myoblasts show disease-related phenotypes with patient-to-patient variability, including aberrant expression of inflammation or immune-response genes and collagens, increased BMP/TGFb 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.