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Nat Cell Biol. 2018 Jan;20(1):46-57. doi: 10.1038/s41556-017-0010-2. Epub 2017 Dec 18.

ERBB3 and NGFR mark a distinct skeletal muscle progenitor cell in human development and hPSCs.

Hicks MR1,2,3, Hiserodt J3, Paras K3, Fujiwara W3, Eskin A2,4, Jan M1,2,3, Xi H1,2,3, Young CS1,2,5, Evseenko D6, Nelson SF2,4,5, Spencer MJ1,2,5,7, Handel BV6, Pyle AD8,9,10,11.

Author information

1
Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA, USA.
2
Center for Duchenne Muscular Dystrophy, University of California, Los Angeles, CA, USA.
3
Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA, USA.
4
Department of Human Genetics, University of California, Los Angeles, CA, USA.
5
Molecular Biology Interdepartmental Program, University of California, Los Angeles, CA, USA.
6
Department of Orthopaedic Surgery, Keck School of Medicine, Stem Cell Research and Regenerative Medicine, University of Southern California, Los Angeles, CA, USA.
7
Department of Neurology, University of California, Los Angeles, CA, USA.
8
Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA, USA. apyle@mednet.ucla.edu.
9
Center for Duchenne Muscular Dystrophy, University of California, Los Angeles, CA, USA. apyle@mednet.ucla.edu.
10
Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA, USA. apyle@mednet.ucla.edu.
11
Molecular Biology Interdepartmental Program, University of California, Los Angeles, CA, USA. apyle@mednet.ucla.edu.

Abstract

Human pluripotent stem cells (hPSCs) can be directed to differentiate into skeletal muscle progenitor cells (SMPCs). However, the myogenicity of hPSC-SMPCs relative to human fetal or adult satellite cells remains unclear. We observed that hPSC-SMPCs derived by directed differentiation are less functional in vitro and in vivo compared to human satellite cells. Using RNA sequencing, we found that the cell surface receptors ERBB3 and NGFR demarcate myogenic populations, including PAX7 progenitors in human fetal development and hPSC-SMPCs. We demonstrated that hPSC skeletal muscle is immature, but inhibition of transforming growth factor-β signalling during differentiation improved fusion efficiency, ultrastructural organization and the expression of adult myosins. This enrichment and maturation strategy restored dystrophin in hundreds of dystrophin-deficient myofibres after engraftment of CRISPR-Cas9-corrected Duchenne muscular dystrophy human induced pluripotent stem cell-SMPCs. The work provides an in-depth characterization of human myogenesis, and identifies candidates that improve the in vivo myogenic potential of hPSC-SMPCs to levels that are equal to directly isolated human fetal muscle cells.

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