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Cell Stem Cell. 2019 Dec 5;25(6):797-813.e9. doi: 10.1016/j.stem.2019.11.004.

Hic1 Defines Quiescent Mesenchymal Progenitor Subpopulations with Distinct Functions and Fates in Skeletal Muscle Regeneration.

Author information

1
Department of Cellular and Physiological Sciences, 2222 Health Sciences Mall, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada; School of Biomedical Engineering and the Biomedical Research Centre, 2222 Health Sciences Mall, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada.
2
Department of Cellular and Physiological Sciences, 2222 Health Sciences Mall, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada.
3
Research Division, Shriners Hospital for Children, Portland, OR 97239, USA.
4
Department of Medical Genetics, 2222 Health Sciences Mall, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada; School of Biomedical Engineering and the Biomedical Research Centre, 2222 Health Sciences Mall, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada.
5
Department of Cellular and Physiological Sciences, 2222 Health Sciences Mall, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada; School of Biomedical Engineering and the Biomedical Research Centre, 2222 Health Sciences Mall, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada. Electronic address: tunderhi@brc.ubc.ca.

Abstract

Many adult tissues contain resident stem cells, such as the Pax7+ satellite cells within skeletal muscle, that regenerate parenchymal elements following damage. Tissue-resident mesenchymal progenitors (MPs) also participate in regeneration, although their function and fate in this process are unclear. Here, we identify Hypermethylated in cancer 1 (Hic1) as a marker of MPs in skeletal muscle and further show that Hic1 deletion leads to MP hyperplasia. Single-cell RNA-seq and ATAC-seq analysis of Hic1+ MPs in skeletal muscle shows multiple subpopulations, which we further show have distinct functions and lineage potential. Hic1+ MPs orchestrate multiple aspects of skeletal muscle regeneration by providing stage-specific immunomodulation and trophic and mechanical support. During muscle regeneration, Hic1+ derivatives directly contribute to several mesenchymal compartments including Col22a1-expressing cells within the myotendinous junction. Collectively, these findings demonstrate that HIC1 regulates MP quiescence and identifies MP subpopulations with transient and enduring roles in muscle regeneration.

KEYWORDS:

lineage tracing; mesenchymal progenitors; myotendinous junction; pericytes; quiescence; scATAC-seq; scRNA-seq; skeletal muscle; tendon; tissue regeneration

PMID:
31809738
PMCID:
PMC6941576
[Available on 2020-12-05]
DOI:
10.1016/j.stem.2019.11.004
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