Three-Dimensional Human iPSC-Derived Artificial Skeletal Muscles Model Muscular Dystrophies and Enable Multilineage Tissue Engineering

TLDR

Generating human skeletal muscle models is instrumental for investigating muscle pathology and therapy. The study reports generating three‑dimensional artificial skeletal muscle tissue from human pluripotent stem cells, including iPSCs derived from patients with Duchenne, limb‑girdle, and congenital muscular dystrophies. 3D skeletal myogenic differentiation was induced within hydrogels under tension to align myofibers. Artificial muscles reproduced human skeletal muscle traits, were transplantable into immunodeficient mice, faithfully modeled severe dystrophic cellular hallmarks, and enabled creation of fully human, multilineage iPSC‑derived muscle constructs with endothelial cells, pericytes, and motor neurons, establishing a platform for disease modeling and regenerative therapies.

Abstract

Generating human skeletal muscle models is instrumental for investigating muscle pathology and therapy. Here, we report the generation of three-dimensional (3D) artificial skeletal muscle tissue from human pluripotent stem cells, including induced pluripotent stem cells (iPSCs) from patients with Duchenne, limb-girdle, and congenital muscular dystrophies. 3D skeletal myogenic differentiation of pluripotent cells was induced within hydrogels under tension to provide myofiber alignment. Artificial muscles recapitulated characteristics of human skeletal muscle tissue and could be implanted into immunodeficient mice. Pathological cellular hallmarks of incurable forms of severe muscular dystrophy could be modeled with high fidelity using this 3D platform. Finally, we show generation of fully human iPSC-derived, complex, multilineage muscle models containing key isogenic cellular constituents of skeletal muscle, including vascular endothelial cells, pericytes, and motor neurons. These results lay the foundation for a human skeletal muscle organoid-like platform for disease modeling, regenerative medicine, and therapy development.