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. Wells; Thomas Eschenhagen; Francesco Saverio Tedesco

doi:10.1016/j.celrep.2018.03.091

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

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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 language	English
Pages (from-to)	899-908
Number of pages	10
Journal	Cell Reports
Volume	23
Issue number	3
Early online date	17 Apr 2018
DOIs	https://doi.org/10.1016/j.celrep.2018.03.091
Publication status	E-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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Three-Dimensional Human iPSC-Derived_MAFFIOLETTI_Published17April2018_GOLD VoR (CC BY)Final published version, 5.21 MBLicence: CC BY

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Maffioletti, S. M., Sarcar, S., Henderson, A. B. H., Mannhardt, I., Pinton, L., Moyle, L. A., Steele-Stallard, H., Cappellari, O., Wells, K. E., Ferrari, G., Mitchell, J. S., Tyzack, G. E., Kotiadis, V. N., Khedr, M., Ragazzi, M., Wang, W., Duchen, M. R., Patani, R., Zammit, P. S., ... Tedesco, F. S. (2018). Three-Dimensional Human iPSC-Derived Artificial Skeletal Muscles Model Muscular Dystrophies and Enable Multilineage Tissue Engineering. Cell Reports, 23(3), 899-908. Advance online publication. https://doi.org/10.1016/j.celrep.2018.03.091

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

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.",

keywords = "skeletal muscle, pluripotent stem cells, iPS cells, myogenic differentiation, tissue engineering, disease modeling, muscular dystrophy, organoids",

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

year = "2018",

month = apr,

day = "17",

doi = "10.1016/j.celrep.2018.03.091",

language = "English",

volume = "23",

pages = "899--908",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Elsevier BV",

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Maffioletti, SM, Sarcar, S, Henderson, ABH, Mannhardt, I, Pinton, L , Moyle, LA, Steele-Stallard, H, Cappellari, O, Wells, KE, Ferrari, G, Mitchell, JS, Tyzack, GE, Kotiadis, VN, Khedr, M, Ragazzi, M, Wang, W, Duchen, MR, Patani, R, Zammit, PS, Wells, DJ, Eschenhagen, T & Tedesco, FS 2018, 'Three-Dimensional Human iPSC-Derived Artificial Skeletal Muscles Model Muscular Dystrophies and Enable Multilineage Tissue Engineering', Cell Reports, vol. 23, no. 3, pp. 899-908. https://doi.org/10.1016/j.celrep.2018.03.091

TY - JOUR

T1 - Three-Dimensional Human iPSC-Derived Artificial Skeletal Muscles Model Muscular Dystrophies and Enable Multilineage Tissue Engineering

AU - Maffioletti, Sara Martina

AU - Sarcar, Shilpita

AU - Henderson, Alexander B.H.

AU - Mannhardt, Ingra

AU - Pinton, Luca

AU - Moyle, Louise Anne

AU - Steele-Stallard, Heather

AU - Cappellari, Ornella

AU - Wells, Kim E.

AU - Ferrari, Giulia

AU - Mitchell, Jamie S.

AU - Tyzack, Giulia E.

AU - Kotiadis, Vassilios N.

AU - Khedr, Moustafa

AU - Ragazzi, Martina

AU - Wang, Weixin

AU - Duchen, Michael R.

AU - Patani, Rickie

AU - Zammit, Peter S.

AU - Wells, Dominic J.

AU - Eschenhagen, Thomas

AU - Tedesco, Francesco Saverio

PY - 2018/4/17

Y1 - 2018/4/17

N2 - 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.

AB - 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.

KW - skeletal muscle

KW - pluripotent stem cells

KW - iPS cells

KW - myogenic differentiation

KW - tissue engineering

KW - disease modeling

KW - muscular dystrophy

KW - organoids

U2 - 10.1016/j.celrep.2018.03.091

DO - 10.1016/j.celrep.2018.03.091

M3 - Article

SN - 2211-1247

VL - 23

SP - 899

EP - 908

JO - Cell Reports

JF - Cell Reports

IS - 3

ER -

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

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Keywords

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