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

Overview

Journal Cell Stem Cell

Publisher Cell Press

Specialty Cell Biology

Date 2019 Dec 7

PMID 31809738

Citations 96

Authors

R Wilder Scott

Martin Arostegui

Ronen Schweitzer

Fabio M V Rossi

T Michael Underhill

Affiliations

Soon will be listed here.

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.

Citing Articles

The role of oxidative stress-mediated fibro-adipogenic progenitor senescence in skeletal muscle regeneration and repair.

Yao Y, Luo Y, Liang X, Zhong L, Wang Y, Hong Z Stem Cell Res Ther. 2025; 16(1):104.

PMID: 40025535 PMC: 11872320. DOI: 10.1186/s13287-025-04242-4.

Brain pericytes and perivascular fibroblasts are stromal progenitors with dual functions in cerebrovascular regeneration after stroke.

Bernier L, Hefendehl J, Scott R, Tung L, Lewis C, Soliman H Nat Neurosci. 2025; 28(3):517-535.

PMID: 39962273 DOI: 10.1038/s41593-025-01872-y.

Pdgfrα stromal cells, a key regulator for tissue homeostasis and dysfunction in distinct organs.

Kang X, Zhao K, Huang Z, Fukada S, Qi X, Miao H Genes Dis. 2025; 12(2):101264.

PMID: 39759120 PMC: 11696774. DOI: 10.1016/j.gendis.2024.101264.

Erroneous Differentiation of Tendon Stem/Progenitor Cells in the Pathogenesis of Tendinopathy: Current Evidence and Future Perspectives.

Gao Y, Wang H, Shi L, Lu P, Dai G, Zhang M Stem Cell Rev Rep. 2024; 21(2):423-453.

PMID: 39579294 DOI: 10.1007/s12015-024-10826-z.

Beyond the bulk: overview and novel insights into the dynamics of muscle satellite cells during muscle regeneration.

Byun W, Lee J, Baek J Inflamm Regen. 2024; 44(1):39.

PMID: 39327631 PMC: 11426090. DOI: 10.1186/s41232-024-00354-1.

References

Joe A, Yi L, Natarajan A, Le Grand F, So L, Wang J . Muscle injury activates resident fibro/adipogenic progenitors that facilitate myogenesis. Nat Cell Biol. 2010; 12(2):153-63. PMC: 4580288. DOI: 10.1038/ncb2015. View

Uezumi A, Ito T, Morikawa D, Shimizu N, Yoneda T, Segawa M . Fibrosis and adipogenesis originate from a common mesenchymal progenitor in skeletal muscle. J Cell Sci. 2011; 124(Pt 21):3654-64. DOI: 10.1242/jcs.086629. View

Gunther S, Kim J, Kostin S, Lepper C, Fan C, Braun T . Myf5-positive satellite cells contribute to Pax7-dependent long-term maintenance of adult muscle stem cells. Cell Stem Cell. 2013; 13(5):590-601. PMC: 4082715. DOI: 10.1016/j.stem.2013.07.016. View

Huang A, Lu H, Schweitzer R . Molecular regulation of tendon cell fate during development. J Orthop Res. 2015; 33(6):800-12. DOI: 10.1002/jor.22834. View

Qiu X, Mao Q, Tang Y, Wang L, Chawla R, Pliner H . Reversed graph embedding resolves complex single-cell trajectories. Nat Methods. 2017; 14(10):979-982. PMC: 5764547. DOI: 10.1038/nmeth.4402. View

Uezumi A, Fukada S, Yamamoto N, Takeda S, Tsuchida K . Mesenchymal progenitors distinct from satellite cells contribute to ectopic fat cell formation in skeletal muscle. Nat Cell Biol. 2010; 12(2):143-52. DOI: 10.1038/ncb2014. View

Schneider R, Mullally A, Dugourd A, Peisker F, Hoogenboezem R, van Strien P . Gli1 Mesenchymal Stromal Cells Are a Key Driver of Bone Marrow Fibrosis and an Important Cellular Therapeutic Target. Cell Stem Cell. 2017; 20(6):785-800.e8. PMC: 6485654. DOI: 10.1016/j.stem.2017.03.008. View

Younesy H, Moller T, Lorincz M, Karimi M, Jones S . VisRseq: R-based visual framework for analysis of sequencing data. BMC Bioinformatics. 2015; 16 Suppl 11:S2. PMC: 4559603. DOI: 10.1186/1471-2105-16-S11-S2. View

Satija R, Farrell J, Gennert D, Schier A, Regev A . Spatial reconstruction of single-cell gene expression data. Nat Biotechnol. 2015; 33(5):495-502. PMC: 4430369. DOI: 10.1038/nbt.3192. View

10.

Yin H, Price F, Rudnicki M . Satellite cells and the muscle stem cell niche. Physiol Rev. 2013; 93(1):23-67. PMC: 4073943. DOI: 10.1152/physrev.00043.2011. View

11.

Bianco P . "Mesenchymal" stem cells. Annu Rev Cell Dev Biol. 2014; 30:677-704. DOI: 10.1146/annurev-cellbio-100913-013132. View

12.

Worthley D, Churchill M, Compton J, Tailor Y, Rao M, Si Y . Gremlin 1 identifies a skeletal stem cell with bone, cartilage, and reticular stromal potential. Cell. 2015; 160(1-2):269-84. PMC: 4436082. DOI: 10.1016/j.cell.2014.11.042. View

13.

Zhao C, Cai S, Shin K, Lim A, Kalisky T, Lu W . Stromal activity coordinates a niche signaling program for mammary epithelial stem cells. Science. 2017; 356(6335). DOI: 10.1126/science.aal3485. View

14.

Van Rechem C, Boulay G, Pinte S, Stankovic-Valentin N, Guerardel C, Leprince D . Differential regulation of HIC1 target genes by CtBP and NuRD, via an acetylation/SUMOylation switch, in quiescent versus proliferating cells. Mol Cell Biol. 2010; 30(16):4045-59. PMC: 2916445. DOI: 10.1128/MCB.00582-09. View

15.

Zou Y, Zwolanek D, Izu Y, Gandhy S, Schreiber G, Brockmann K . Recessive and dominant mutations in COL12A1 cause a novel EDS/myopathy overlap syndrome in humans and mice. Hum Mol Genet. 2013; 23(9):2339-52. PMC: 3976332. DOI: 10.1093/hmg/ddt627. View

16.

Coller H, Sang L, Roberts J . A new description of cellular quiescence. PLoS Biol. 2006; 4(3):e83. PMC: 1393757. DOI: 10.1371/journal.pbio.0040083. View

17.

Scott R, Underhill T . Methods and Strategies for Lineage Tracing of Mesenchymal Progenitor Cells. Methods Mol Biol. 2016; 1416:171-203. DOI: 10.1007/978-1-4939-3584-0_10. View

18.

Zhou B, Yue R, Murphy M, Peyer J, Morrison S . Leptin-receptor-expressing mesenchymal stromal cells represent the main source of bone formed by adult bone marrow. Cell Stem Cell. 2014; 15(2):154-68. PMC: 4127103. DOI: 10.1016/j.stem.2014.06.008. View

19.

Wales M, Biel M, El Deiry W, Nelkin B, Issa J, Cavenee W . p53 activates expression of HIC-1, a new candidate tumour suppressor gene on 17p13.3. Nat Med. 1995; 1(6):570-7. DOI: 10.1038/nm0695-570. View

20.

Pryce B, Brent A, Murchison N, Tabin C, Schweitzer R . Generation of transgenic tendon reporters, ScxGFP and ScxAP, using regulatory elements of the scleraxis gene. Dev Dyn. 2007; 236(6):1677-82. DOI: 10.1002/dvdy.21179. View