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

Sara Martina Maffioletti, Shilpita Sarcar, Alexander B.H. Henderson, Ingra Mannhardt, Luca Pinton, Louise Anne Moyle, Heather Steele-Stallard, Ornella Cappellari, Kim E. Wells, Giulia Ferrari, Jamie S. Mitchell, Giulia E. Tyzack, Vassilios N. Kotiadis, Moustafa Khedr, Martina Ragazzi, Weixin Wang, Michael R. Duchen, Rickie Patani, Peter S. Zammit, Dominic J. WellsThomas Eschenhagen, Francesco Saverio Tedesco

Research output: Contribution to journalArticlepeer-review

208 Citations (Scopus)
637 Downloads (Pure)

Abstract

Summary
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.
Original languageEnglish
Pages (from-to)899-908
Number of pages10
JournalCell Reports
Volume23
Issue number3
Early online date17 Apr 2018
DOIs
Publication statusE-pub ahead of print - 17 Apr 2018

Keywords

  • skeletal muscle
  • pluripotent stem cells
  • iPS cells
  • myogenic differentiation
  • tissue engineering
  • disease modeling
  • muscular dystrophy
  • organoids

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