Journal
NATURE CELL BIOLOGY
Volume 20, Issue 1, Pages 46-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41556-017-0010-2
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Funding
- CFAR Flow Cytometry Core (NIH) [P30CA016042, 5P30AI028697]
- UCLA Humanized Mouse Core (CFAR) [NIAID AI028697]
- BSCRC and Schaffer Fellowship
- CDMD-Cure Duchenne Fellowship
- CDMD-NIH Paul Wellstone Center Training Fellowship [U54 AR052646]
- NIH [K01AR061415]
- Department of Defense (DoD) grant [W81XWH-13-1-0465]
- California Institute for Regenerative Medicine (CIRM) grant [RB5-07230]
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) [R01AR064327]
- NIAMS [5P30AR05723]
- CDMD at UCLA
- NIH/NCATS
- UCLA CTSI [UL1TR000124]
- BSCRC Research Award
- Rose Hills Foundation Research Award
- CIRM Inception and CIRM Quest [DISC1-08823, DISC2-08824]
- NATIONAL CANCER INSTITUTE [P30CA016042] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [P30AI028697] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [P30AR057230, U54AR052646, T32AR065972, R01AR064327, K01AR061415, R01AR071734] Funding Source: NIH RePORTER
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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-beta 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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