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

• Published in: Cell reports (Cambridge) Vol. 23; no. 3; pp. 899 - 908
• Main Authors: Maffioletti, Sara Martina, Sarcar, Shilpita, Henderson, Alexander B.H., Mannhardt, Ingra, Pinton, Luca, Moyle, Louise Anne, Steele-Stallard, Heather, Cappellari, Ornella, Wells, Kim E., Ferrari, Giulia, Mitchell, Jamie S., Tyzack, Giulia E., Kotiadis, Vassilios N., Khedr, Moustafa, Ragazzi, Martina, Wang, Weixin, Duchen, Michael R., Patani, Rickie, Zammit, Peter S., Wells, Dominic J., Eschenhagen, Thomas, Tedesco, Francesco Saverio
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.04.2018; Cell Press; Elsevier
• Subjects: Cell Differentiation; Cell Lineage; disease modeling; Humans; Hydrogels - chemistry; Induced Pluripotent Stem Cells - cytology; iPS cells; Models, Biological; Muscle Development; Muscle, Skeletal - cytology; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Muscular Dystrophies - metabolism; Muscular Dystrophies - pathology; muscular dystrophy; myogenic differentiation; organoids; pluripotent stem cells; skeletal muscle; Tissue Engineering; Tissue Scaffolds - chemistry; tissue engineering; muscular dystrophy; pluripotent stem cells; myogenic differentiation; organoids; disease modeling; skeletal muscle; iPS cells
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2018.03.091

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. [Display omitted] •Human iPSC-derived 3D artificial muscles show features of normal skeletal muscle•Multiple muscular dystrophy iPSC lines can be differentiated in 3D artificial muscles•Artificial muscle constructs model severe, incurable forms of muscular dystrophy•Isogenic vascular-like networks and motor neurons develop within artificial muscles Maffioletti et al. generate human 3D artificial skeletal muscles from healthy donors and patient-specific pluripotent stem cells. These human artificial muscles accurately model severe genetic muscle diseases. They can be engineered to include other cell types present in skeletal muscle, such as vascular cells and motor neurons.