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

• DOI: 10.1016/j.celrep.2018.03.091
• Publication Date: 2018-04-17T15:41:04Z
• Authors: Sara Martina Maff...; Shilpita Sarcar; Alexander B.H. He...; Ingra Mannhardt; Luca Pinton; Louise Anne Moyle; Heather Steele-St...; Ornella Cappellari; Kim E. Wells; Giulia Ferrari; Jamie S. Mitchell; Giulia E. Tyzack; Vassilios N. Koti...; Moustafa Khedr; Martina Ragazzi; Weixin Wang; Michael R. Duchen; Rickie Patani; Peter S. Zammit; Dominic J. Wells; Thomas Eschenhagen; Francesco Saverio...
• Keywords: muscular dystrophy; 0301 basic medicine; 570; QH301-705.5; organoid; Induced Pluripotent Stem Cells; 610; myogenic differentiation; Muscle Development; iPS cell; Models, Biological; Induced Pluripotent Stem Cell; Article; Muscular Dystrophies; 03 medical and health sciences; Tissue Scaffold; Models; disease modeling; Humans; pluripotent stem cell; Cell Lineage; skeletal muscle; Biology (General); Muscle, Skeletal; Muscular Dystrophie; organoids; Tissue Engineering; Tissue Scaffolds; Cell Differentiation; Hydrogels; Skeletal; Biological; Hydrogel; iPS cells; Disease modeling; tissue engineering; Muscle; pluripotent stem cells; Human

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.