Abstract
Skeletal muscle stem cells, called satellite cells and defined by the transcription factor PAX7, are responsible for postnatal muscle growth, homeostasis and regeneration. Attempts to utilize the regenerative potential of muscle stem cells for therapeutic purposes so far failed. We previously established the existence of human PAX7-positive cell colonies with high regenerative potential. We now identified PAX7-negative human muscle-derived cell colonies also positive for the myogenic markers desmin and MYF5. These include cells from a patient with a homozygous PAX7 c.86-1G > A mutation (PAX7null). Single cell and bulk transcriptome analysis show high intra- and inter-donor heterogeneity and reveal the endothelial cell marker CLEC14A to be highly expressed in PAX7null cells. All PAX7-negative cell populations, including PAX7null, form myofibers after transplantation into mice, and regenerate muscle after reinjury. Transplanted PAX7neg cells repopulate the satellite cell niche where they re-express PAX7, or, strikingly, CLEC14A. In conclusion, transplanted human cells do not depend on PAX7 for muscle regeneration.
Highlights
Skeletal muscle stem cells, called satellite cells and defined by the transcription factor PAX7, are responsible for postnatal muscle growth, homeostasis and regeneration
We aimed to evaluate the potential of primary human satellite cells and to identify subpopulations suitable for muscle regeneration
Pure myogenic cell populations (n = 103) were isolated from human muscle biopsy specimens obtained from 25 different donors using manual dissection followed by hypothermic treatment (Fig. 1a; Supplementary Tables 1 and 2)
Summary
Skeletal muscle stem cells, called satellite cells and defined by the transcription factor PAX7, are responsible for postnatal muscle growth, homeostasis and regeneration. We previously established the existence of human PAX7-positive cell colonies with high regenerative potential. We identified PAX7-negative human muscle-derived cell colonies positive for the myogenic markers desmin and MYF5. These include cells from a patient with a homozygous PAX7 c.86-1G > A mutation (PAX7null). The CRISPR/Cas[9] technology may allow for precise gene editing in primary cells It is not clear which molecular markers define the cell populations with high myogenic potential. CD133 cells, PW1 cells and mesenchymal stem cells have all been proposed to have myogenic potential, but at least in mice there is no muscle regeneration without Pax7-positive satellite cells[6,7,8]. Regeneration efficiency of myogenic desmin-positive cell populations did not depend on the expression level of PAX7
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