Skip to main content
Log in

Hic1 deletion unleashes quiescent connective tissue stem cells and impairs skeletal muscle regeneration

  • Commentary
  • Published:
Journal of Cell Communication and Signaling Aims and scope

Abstract

Skeletal muscle fibro-adipogenic progenitors (FAPs) are tissue-resident connective tissue cells and the main cellular source of pathological fibro-fatty scar associated with muscle disorders. Although our knowledge about skeletal muscle mesenchymal progenitor cells has exploded in the past decade, we still lack information about their origin, fate, gene regulation, function, and stemness. A recent study by Underhill and colleagues, published in Cell Stem Cell, described the last census of Hic1 mesenchymal progenitor/stem cells in skeletal muscle regeneration, providing valuable results and data to the ever-expanding community of scientists interested in tissue regeneration and fibrosis. This commentary contextualizes and summarizes these exciting new findings.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

References

  • Asli NS, Xaymardan M, Patrick R, Farbehi N, Cornwell J, Forte E, Waardenberg AJ, Janbandhu V, Kesteven S, Chandrakanthan V et al (2018) PDGFRα signaling in cardiac fibroblasts modulates quiescence, metabolism and self-renewal, and promotes anatomical and functional repair. BioRxiv 225979. https://doi.org/10.1101/225979

  • Chen WY, Zeng X, Carter MG, Morrell CN, Chiu Yen R-W, Esteller M, Watkins DN, Herman JG, Mankowski JL, Baylin SB (2003) Heterozygous disruption of Hic1 predisposes mice to a gender-dependent spectrum of malignant tumors. Nat Genet 33(2):197–202. https://doi.org/10.1038/ng1077

    Article  CAS  PubMed  Google Scholar 

  • Contreras O, Rebolledo DL, Oyarzun JE, Olguin HC, Brandan E (2016) Connective tissue cells expressing fibro/adipogenic progenitor markers increase under chronic damage: relevance in fibroblast-myofibroblast differentiation and skeletal muscle fibrosis. Cell Tissue Res 364:647–660

    Article  CAS  Google Scholar 

  • Contreras O, Rossi FM, Brandan E (2019a) Adherent muscle connective tissue fibroblasts are phenotypically and biochemically equivalent to stromal fibro/adipogenic progenitors. Matrix Biol Plus 2:100006. https://doi.org/10.1016/J.MBPLUS.2019.04.003

    Article  Google Scholar 

  • Contreras O, Cruz-Soca M, Theret M, Soliman H, Tung LW, Groppa E, Rossi FM, Brandan E (2019b) Cross-talk between TGF-β and PDGFRα signaling pathways regulates the fate of stromal fibro–adipogenic progenitors. J Cell Sci 132:232157. https://doi.org/10.1242/jcs.232157

    Article  CAS  Google Scholar 

  • Farbehi N, Patrick R, Dorison A, Xaymardan M, Janbandhu V, Wystub-Lis K, Ho JWK, Nordon RE, Harvey RP (2019) Single-cell expression profiling reveals dynamic flux of cardiac stromal, vascular and immune cells in health and injury. eLife 8

  • Fiore D, Judson RN, Low M, Lee S, Zhang E, Hopkins C, Xu P, Lenzi A, Rossi FM, Lemos DR (2016) Pharmacological blockage of fibro/adipogenic progenitor expansion and suppression of regenerative fibrogenesis is associated with impaired skeletal muscle regeneration. Stem Cell Res 17(1):161–169

    Article  CAS  Google Scholar 

  • Fleuriel C, Touka M, Boulay G, Guérardel C, Rood BR, Leprince D (2009) HIC1 (Hypermethylated in Cancer 1) epigenetic silencing in tumors. Int J Biochem Cell Biol 41:26–33

    Article  CAS  Google Scholar 

  • Fu X, Khalil H, Kanisicak O, Boyer JG, Vagnozzi RJ, Maliken BD, Sargent MA, Prasad V, Valiente-Alandi I, Blaxall BC, Molkentin JD (2018) Specialized fibroblast differentiated states underlie scar formation in the infarcted mouse heart. J Clin Invest 128(5):2127–2143. https://doi.org/10.1172/JCI98215

    Article  PubMed  PubMed Central  Google Scholar 

  • Gonzalez D, Contreras O, Rebolledo DL, Espinoza JP, van Zundert B, Brandan E (2017) ALS skeletal muscle shows enhanced TGF-beta signaling, fibrosis and induction of fibro/adipogenic progenitor markers. PLoS One 12:e0177649

    Article  Google Scholar 

  • Joe AW, Yi L, Natarajan A, Le Grand F, So L, Wang J, Rudnicki MA, Rossi FM (2010) Muscle injury activates resident fibro/adipogenic progenitors that facilitate myogenesis. Nat Cell Biol 12:153–163

    Article  CAS  Google Scholar 

  • Kanisicak O, Khalil H, Ivey MJ, Karch J, Maliken BD, Correll RN et al (2016) Genetic lineage tracing defines myofibroblast origin and function in the injured heart. Nat Commun. https://doi.org/10.1038/ncomms12260

  • Lemos DR, Duffield JS (2018) Tissue-resident mesenchymal stromal cells: implications for tissue-specific antifibrotic therapies. Sci Transl Med. https://doi.org/10.1126/scitranslmed.aan5174

  • Lemos DR, Babaeijandaghi F, Low M, Chang CK, Lee ST, Fiore D, Zhang RH, Natarajan A, Nedospasov SA, Rossi FM (2015) Nilotinib reduces muscle fibrosis in chronic muscle injury by promoting TNF-mediated apoptosis of fibro/adipogenic progenitors. Nat Med 21:786–794

    Article  CAS  Google Scholar 

  • Madaro L, Passafaro M, Sala D, Etxaniz U, Lugarini F, Proietti D, Alfonsi MV, Nicoletti C, Gatto S, De Bardi M, Rojas-Garcia R, Giordani L, Marinelli S, Pagliarini V, Sette C, Sacco A, Puri PL (2018) Denervation-activated STAT3-IL-6 signalling in fibro-adipogenic progenitors promotes myofibres atrophy and fibrosis. Nat Cell Biol 20:917–927

    Article  CAS  Google Scholar 

  • Mathew SJ, Hansen JM, Merrell AJ, Murphy MM, Lawson JA, Hutcheson DA, Hansen MS, Angus-Hill M, Kardon G (2011) Connective tissue fibroblasts and Tcf4 regulate myogenesis. Development 138:371–384. https://doi.org/10.1242/dev.057463

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Murphy MM, Lawson JA, Mathew SJ, Hutcheson DA, Kardon G (2011) Satellite cells, connective tissue fibroblasts and their interactions are crucial for muscle regeneration. Development 138:3625–3637. https://doi.org/10.1242/dev.064162

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nassari S, Duprez D, Fournier-Thibault C (2017) Non-myogenic contribution to muscle development and homeostasis: the role of connective tissues. Front Cell Dev Biol 5:22

    Article  Google Scholar 

  • Natarajan A, Lemos DR, Rossi FM (2010) Fibro/adipogenic progenitors: a double-edged sword in skeletal muscle regeneration. Cell Cycle 9:2045–2046

    Article  CAS  Google Scholar 

  • Scott RW, Arostegui M, Schweitzer R, Rossi FMV, Underhill TM (2019) Hic1 defines quiescent Mesenchymal progenitor subpopulations with distinct functions and fates in skeletal muscle regeneration. Cell Stem Cell 25(6):797–813.e9. https://doi.org/10.1016/j.stem.2019.11.004

    Article  CAS  PubMed  Google Scholar 

  • Stricker S, Mathia S, Haupt J, Seemann P, Meier J, Mundlos S (2012) Odd-skipped related genes regulate differentiation of embryonic limb mesenchyme and bone marrow mesenchymal stromal cells. Stem Cells Dev 21(4):623–633

    Article  CAS  Google Scholar 

  • Stumm J, Vallecillo-Garcia P, Vom Hofe-Schneider S, Ollitrault D, Schrewe H, Economides AN, Marazzi G, Sassoon DA, Stricker S (2018) Odd skipped-related 1 (Osr1) identifies muscle-interstitial fibro-adipogenic progenitors (FAPs) activated by acute injury. Stem Cell Res 32:8–16

    Article  CAS  Google Scholar 

  • The Tabula Muris Consortium, Overall coordination, Logistical coordination, Organ collection and processing; Library preparation and sequencing, Computational data analysis, Cell type annotation, Writing group, Supplemental text writing group and Principal investigators (2018) Single cell transcriptomics of 20 mouse organs creates a Tabula Muris. Nature 562:367–372. https://doi.org/10.1038/s41586-018-0590-4

    Article  CAS  Google Scholar 

  • Uezumi A, Fukada S, Yamamoto N, Takeda S, Tsuchida K (2010) Mesenchymal progenitors distinct from satellite cells contribute to ectopic fat cell formation in skeletal muscle. Nat Cell Biol 12:143–152

    Article  CAS  Google Scholar 

  • Uezumi A, Ito T, Morikawa D, Shimizu N, Yoneda T, Segawa M, Yamaguchi M, Ogawa R, Matev MM, Miyagoe-Suzuki Y, Takeda S, Tsujikawa K, Tsuchida K, Yamamoto H, Fukada S (2011) Fibrosis and adipogenesis originate from a common mesenchymal progenitor in skeletal muscle. J Cell Sci 124:3654–3664

    Article  CAS  Google Scholar 

  • Uezumi A, Fukada S, Yamamoto N, Ikemoto-Uezumi M, Nakatani M, Morita M, Yamaguchi A, Yamada H, Nishino I, Hamada Y, Tsuchida K (2014) Identification and characterization of PDGFRalpha+ mesenchymal progenitors in human skeletal muscle. Cell Death Dis 5:e1186

    Article  CAS  Google Scholar 

  • Vallecillo-García P, Orgeur M, Vom Hofe-Schneider S, Stumm J, Kappert V, Ibrahim DM, Börno ST, Hayashi S, Relaix F, Hildebrandt K et al (2018) Odd skipped-related 1 identifies a population of embryonic fibroadipogenic progenitors regulating myogenesis during limb development. Nat Commun 8:1218. https://doi.org/10.1038/s41467-017-01120-3

  • Wosczyna MN, Rando TA (2018) A muscle stem cell support group: coordinated cellular responses in muscle regeneration. Dev Cell 46(2):135–143

    Article  CAS  Google Scholar 

  • Wosczyna MN, Konishi CT, Perez Carbajal EE, Wang TT, Walsh RA, Gan Q, Wagner MW, Rando TA (2019) Mesenchymal Stromal Cells Are Required for Regeneration and Homeostatic Maintenance of Skeletal Muscle. Cell Reports 27 (7):2029-2035.e5

Download references

Acknowledgments

I am grateful to my friend Camilo Riquelme-Guzmán (Center for Regenerative Therapies Dresden (CRTD) - TU Dresden) for proofreading this manuscript. Beca de Doctorado Nacional 21140378 from CONICYT to O.C. supported this work. The funding agency had no role in the design of the study, data collection, analysis, decision to publish, or preparation of the manuscript. I apologize to my colleagues and authors whose work could not be cited or was cited indirectly, due to space restrictions.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Osvaldo Contreras.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Contreras, O. Hic1 deletion unleashes quiescent connective tissue stem cells and impairs skeletal muscle regeneration. J. Cell Commun. Signal. 14, 131–133 (2020). https://doi.org/10.1007/s12079-019-00545-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12079-019-00545-3

Keywords

Navigation