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Identification and characterization of a non-satellite cell muscle resident progenitor during postnatal development

Nature Cell Biology volume 12, pages 257–266 (2010)Cite this article

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Abstract

Satellite cells are resident myogenic progenitors in postnatal skeletal muscle involved in muscle postnatal growth and adult regenerative capacity. Here, we identify and describe a population of muscle-resident stem cells, which are located in the interstitium, that express the cell stress mediator PW1 but do not express other markers of muscle stem cells such as Pax7. PW1+/Pax7− interstitial cells (PICs) are myogenic in vitro and efficiently contribute to skeletal muscle regeneration in vivo as well as generating satellite cells and PICs. Whereas Pax7 mutant satellite cells show robust myogenic potential, Pax7 mutant PICs are unable to participate in myogenesis and accumulate during postnatal growth. Furthermore, we found that PICs are not derived from a satellite cell lineage. Taken together, our findings uncover a new and anatomically identifiable population of muscle progenitors and define a key role for Pax7 in a non-satellite cell population during postnatal muscle growth.

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Figure 1: PW1 identifies two distinct populations in postnatal muscle under the regulation of Pax7.
Figure 2: PICs are enriched in the muscle-resident Sca1+/CD34+ population.
Figure 3: PICs spontaneously convert to skeletal myogenic cells via a Pax7-dependent pathway.
Figure 4: Pax7 is required for PICs to participate in myogenesis.
Figure 5: PICs are bipotent and give rise to smooth and skeletal muscle.
Figure 6: PICs are myogenic and recolonize the PIC niche in vivo.
Figure 7: PICs are not derived from satellite cells.

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References

  1. Endo, T. Stem cells and plasticity of skeletal muscle cell differentiation: potential application to cell therapy for degenerative muscular diseases. Regen Med. 2, 243–256 (2007).

    Article  CAS  Google Scholar 

  2. Montarras, D. et al. Direct isolation of satellite cells for skeletal muscle regeneration. Science 309, 2064–2067 (2005).

    Article  CAS  Google Scholar 

  3. Chen, J. C. & Goldhamer, D. J. Skeletal muscle stem cells. Reprod. Biol. Endocrinol. 1, 101 (2003).

    Article  Google Scholar 

  4. Asakura, A. Stem cells in adult skeletal muscle. Trends Cardiovasc. Med. 13, 123–128 (2003).

    Article  CAS  Google Scholar 

  5. Bischoff, R. Regeneration of single skeletal muscle fibers in vitro. Anat. Rec. 182, 215–235 (1975).

    Article  CAS  Google Scholar 

  6. Peault, B. et al. Stem and progenitor cells in skeletal muscle development, maintenance, and therapy. Mol. Ther. 15, 867–877 (2007).

    Article  CAS  Google Scholar 

  7. Charge, S. B. & Rudnicki, M. A. Cellular and molecular regulation of muscle regeneration. Physiol. Rev. 84, 209–238 (2004).

    Article  CAS  Google Scholar 

  8. Seale, P. et al. Pax7 is required for the specification of myogenic satellite cells. Cell 102, 777–786 (2000).

    Article  CAS  Google Scholar 

  9. Collins, C. A. et al. Stem cell function, self-renewal, and behavioral heterogeneity of cells from the adult muscle satellite cell niche. Cell 122, 289–301 (2005).

    Article  CAS  Google Scholar 

  10. Bischoff, R. Proliferation of muscle satellite cells on intact myofibers in culture. Dev. Biol. 115, 129–139 (1986).

    Article  CAS  Google Scholar 

  11. Hill, M., Wernig, A. & Goldspink, G. Muscle satellite (stem) cell activation during local tissue injury and repair. J. Anat. 203, 89–99 (2003).

    Article  CAS  Google Scholar 

  12. Relaix, F., Rocancourt, D., Mansouri, A. & Buckingham, M. A Pax3/Pax7-dependent population of skeletal muscle progenitor cells. Nature 435, 948–953 (2005).

    Article  CAS  Google Scholar 

  13. Zammit, P. S., Partridge, T. A. & Yablonka-Reuveni, Z. The skeletal muscle satellite cell: the stem cell that came in from the cold. J. Histochem. Cytochem. 54, 1177–1191 (2006).

    Article  CAS  Google Scholar 

  14. Mauro, A. Satellite cell of skeletal muscle fibers. J. Biophys. Biochem. Cytol. 9, 493–495 (1961).

    Article  CAS  Google Scholar 

  15. Irintchev, A., Zeschnigk, M., Starzinski-Powitz, A. & Wernig, A. Expression pattern of M-cadherin in normal, denervated, and regenerating mouse muscles. Dev. Dyn. 199, 326–337 (1994).

    Article  CAS  Google Scholar 

  16. Gros, J., Manceau, M., Thome, V. & Marcelle, C. A common somitic origin for embryonic muscle progenitors and satellite cells. Nature 435, 954–958 (2005).

    Article  CAS  Google Scholar 

  17. Oustanina, S., Hause, G. & Braun, T. Pax7 directs postnatal renewal and propagation of myogenic satellite cells but not their specification. EMBO J. 23, 3430–3439 (2004).

    Article  CAS  Google Scholar 

  18. Kuang, S., Kuroda, K., Le Grand, F. & Rudnicki, M. A. Asymmetric self-renewal and commitment of satellite stem cells in muscle. Cell 129, 999–1010 (2007).

    Article  CAS  Google Scholar 

  19. Relaix, F. et al. Pax3 and Pax7 have distinct and overlapping functions in adult muscle progenitor cells. J. Cell Biol. 172, 91–102 (2006).

    Article  CAS  Google Scholar 

  20. Olguin, H. C. & Olwin, B. B. Pax-7 up-regulation inhibits myogenesis and cell cycle progression in satellite cells: a potential mechanism for self-renewal. Dev. Biol. 275, 375–388 (2004).

    Article  CAS  Google Scholar 

  21. Zammit, P. S. et al. Muscle satellite cells adopt divergent fates: a mechanism for self-renewal? J. Cell Biol. 166, 347–357 (2004).

    Article  CAS  Google Scholar 

  22. Lepper, C., Conway, S. J. & Fan, C. M. Adult satellite cells and embryonic muscle progenitors have distinct genetic requirements. Nature (2009).

  23. Asakura, A., Seale, P., Girgis-Gabardo, A. & Rudnicki, M. A. Myogenic specification of side population cells in skeletal muscle. J. Cell Biol. 159, 123–134 (2002).

    Article  CAS  Google Scholar 

  24. De Angelis, L. et al. Skeletal myogenic progenitors originating from embryonic dorsal aorta coexpress endothelial and myogenic markers and contribute to postnatal muscle growth and regeneration. J. Cell Biol. 147, 869–878 (1999).

    Article  CAS  Google Scholar 

  25. LaBarge, M. A. & Blau, H. M. Biological progression from adult bone marrow to mononucleate muscle stem cell to multinucleate muscle fiber in response to injury. Cell 111, 589–601 (2002).

    Article  CAS  Google Scholar 

  26. Tamaki, T. et al. Skeletal Muscle-Derived CD34+/45- and CD34-/45- Stem Cells Are Situated Hierarchically Upstream of Pax7+ Cells. Stem Cells Dev. (2008).

  27. Lee, J. Y. et al. Clonal isolation of muscle-derived cells capable of enhancing muscle regeneration and bone healing. J. Cell Biol. 150, 1085–1100 (2000).

    Article  CAS  Google Scholar 

  28. Torrente, Y. et al. Intraarterial injection of muscle-derived CD34(+)Sca-1(+) stem cells restores dystrophin in mdx mice. J. Cell Biol. 152, 335–348 (2001).

    Article  CAS  Google Scholar 

  29. Polesskaya, A., Seale, P. & Rudnicki, M. A. Wnt signaling induces the myogenic specification of resident CD45+ adult stem cells during muscle regeneration. Cell 113, 841–852 (2003).

    Article  CAS  Google Scholar 

  30. Dellavalle, A. et al. Pericytes of human skeletal muscle are myogenic precursors distinct from satellite cells. Nature Cell Biol. 9, 255–267 (2007).

    Article  CAS  Google Scholar 

  31. Relaix, F. et al. Pw1, a novel zinc finger gene implicated in the myogenic and neuronal lineages. Dev. Biol. 177, 383–396 (1996).

    Article  CAS  Google Scholar 

  32. Schwarzkopf, M., Coletti, D., Sassoon, D. & Marazzi, G. Muscle cachexia is regulated by a p53-PW1/Peg3-dependent pathway. Genes Dev. 20, 3440–3452 (2006).

    Article  CAS  Google Scholar 

  33. Nicolas, N., Marazzi, G., Kelley, K. & Sassoon, D. Embryonic deregulation of muscle stress signaling pathways leads to altered postnatal stem cell behavior and a failure in postnatal muscle growth. Dev. Biol. 281, 171–183 (2005).

    Article  CAS  Google Scholar 

  34. Coletti, D., Yang, E., Marazzi, G. & Sassoon, D. TNFalpha inhibits skeletal myogenesis through a PW1-dependent pathway by recruitment of caspase pathways. Embo J. 21, 631–642 (2002).

    Article  CAS  Google Scholar 

  35. Coletti, D., Moresi, V., Adamo, S., Molinaro, M. & Sassoon, D. Tumor necrosis factor-alpha gene transfer induces cachexia and inhibits muscle regeneration. Genesis 43, 119–127 (2005).

    Article  Google Scholar 

  36. Relaix, F. et al. Pw1/Peg3 is a potential cell death mediator and cooperates with Siah1a in p53-mediated apoptosis. Proc. Natl Acad. Sci. U S. A 97, 2105–2110 (2000).

    Article  CAS  Google Scholar 

  37. Relaix, F., Wei, X. J., Wu, X. & Sassoon, D. A. Peg3/Pw1 is an imprinted gene involved in the TNF-NFkappaB signal transduction pathway. Nature Genet. 18, 287–291 (1998).

    Article  CAS  Google Scholar 

  38. Seale, P., Ishibashi, J., Scime, A. & Rudnicki, M. A. Pax7 is necessary and sufficient for the myogenic specification of CD45+:Sca1+ stem cells from injured muscle. PLoS Biol. 2, E130 (2004).

    Article  Google Scholar 

  39. Moura-Neto, V. et al. A 28-bp negative element with multiple factor-binding activity controls expression of the vimentin-encoding gene. Gene 168, 261–266 (1996).

    Article  CAS  Google Scholar 

  40. Sax, C. M., Farrell, F. X. & Zehner, Z. E. Down-regulation of vimentin gene expression during myogenesis is controlled by a 5′-flanking sequence. Gene 78, 235–242 (1989).

    Article  CAS  Google Scholar 

  41. Ontell, M. & Kozeka, K. The organogenesis of murine striated muscle: a cytoarchitectural study. Am. J. Anat. 171, 133–148 (1984).

    Article  CAS  Google Scholar 

  42. Ontell, M., Hughes, D. & Bourke, D. Morphometric analysis of the developing mouse soleus muscle. Am. J. Anat. 181, 279–288 (1988).

    Article  CAS  Google Scholar 

  43. Hughes, D. S. & Ontell, M. Morphometric analysis of the developing, murine aneural soleus muscle. Dev. Dyn. 193, 175–184 (1992).

    Article  CAS  Google Scholar 

  44. Sherwood, R. I. et al. Isolation of adult mouse myogenic progenitors: functional heterogeneity of cells within and engrafting skeletal muscle. Cell 119, 543–554 (2004).

    Article  CAS  Google Scholar 

  45. Sacco, A., Doyonnas, R., Kraft, P., Vitorovic, S. & Blau, H. M. Self-renewal and expansion of single transplanted muscle stem cells. Nature 456, 502–506 (2008).

    Article  CAS  Google Scholar 

  46. Buckingham, M. et al. The formation of skeletal muscle: from somite to limb. J. Anat. 202, 59–68 (2003).

    Article  Google Scholar 

  47. Tamaki, T. et al. Identification of myogenic-endothelial progenitor cells in the interstitial spaces of skeletal muscle. J. Cell Biol. 157, 571–577 (2002).

    Article  CAS  Google Scholar 

  48. Tamaki, T., Akatsuka, A., Yoshimura, S., Roy., R. R. & Edgerton, V. R. New fiber formation in the interstitial spaces of rat skeletal muscle during postnatal growth. J. Histochem. Cytochem. 50, 1097–1111 (2002).

    Article  CAS  Google Scholar 

  49. Campion, D. R., Richardson, R. L., Kraeling, R. R. & Reagan, J. O. Changes in the satellite cell population in fetal pig skeletal muscle. J. Anim. Sci. 48, 1109–1115 (1979).

    Article  CAS  Google Scholar 

  50. Asakura, A., Komaki, M. & Rudnicki, M. Muscle satellite cells are multipotential stem cells that exhibit myogenic, osteogenic, and adipogenic differentiation. Differentiation 68, 245–253 (2001).

    Article  CAS  Google Scholar 

  51. Nowak, J. A., Polak, L., Pasolli, H. A. & Fuchs, E. Hair follicle stem cells are specified and function in early skin morphogenesis. Cell Stem Cell 3, 33–43 (2008).

    Article  CAS  Google Scholar 

  52. Fuchs, E. & Horsley, V. More than one way to skin. Genes Dev. 22, 976–985 (2008).

    Article  CAS  Google Scholar 

  53. Yamaguchi, A. et al. Peg3/Pw1 is involved in p53-mediated cell death pathway in brain ischemia/hypoxia. J. Biol. Chem. 277, 623–629 (2002).

    Article  CAS  Google Scholar 

  54. Johnson, M. D., Wu, X., Aithmitti, N. & Morrison, R. S. Peg3/Pw1 is a mediator between p53 and Bax in DNA damage-induced neuronal death. J. Biol. Chem. 277, 23000–23007 (2002).

    Article  CAS  Google Scholar 

  55. Deng, Y. & Wu, X. Peg3/Pw1 promotes p53-mediated apoptosis by inducing Bax translocation from cytosol to mitochondria. Proc. Natl Acad. Sci. USA 97, 12050–12055 (2000).

    Article  CAS  Google Scholar 

  56. Mansouri, A., Stoykova, A., Torres, M. & Gruss, P. Dysgenesis of cephalic neural crest derivatives in Pax7-/- mutant mice. Development 122, 831–838 (1996).

    CAS  PubMed  Google Scholar 

  57. Wright, D. E. et al. Cyclophosphamide/granulocyte colony-stimulating factor causes selective mobilization of bone marrow hematopoietic stem cells into the blood after M phase of the cell cycle. Blood 97, 2278–2285 (2001).

    Article  CAS  Google Scholar 

  58. Montarras, D., Lindon, C., Pinset, C. & Domeyne, P. Cultured myf5 null and myoD null muscle precursor cells display distinct growth defects. Biol. Cell 92, 565–572 (2000).

    Article  CAS  Google Scholar 

  59. McGeachie, J. K. & Grounds, M. D. Initiation and duration of muscle precursor replication after mild and severe injury to skeletal muscle of mice. An autoradiographic study. Cell Tissue Res. 248, 125–130 (1987).

    Article  CAS  Google Scholar 

  60. Sanes, J. R., Rubenstein, J. L. & Nicolas, J. F. Use of a recombinant retrovirus to study post-implantation cell lineage in mouse embryos. EMBO J. 5, 3133–3142 (1986).

    Article  CAS  Google Scholar 

  61. Jackson, K. A., Snyder, D. S. and Goodell, M. A. Skeletal muscle fiber-specific green autofluorescence: potential for stem cell engraftment artifacts. Stem Cells 22, 180–187 (2004).

    Article  Google Scholar 

Download references

Acknowledgements

We gratefully thank F. Relaix for fruitful discussions and critical reading of the manuscript. We thank A. Galy, E. Negroni and L. Arandel for technical advice and C. Blanc (Cytométrie en Flux platform, Institut Fédératif de Recherche 113) for FACs assistance. This work was supported by a grant from the NIH (NCI PO1 CA80058-06, subproject 3), a French Ministry of Research 'Chaire d'Excellence' to D.S. and the Muscular Dystrophy Association of America to D.S. and E.R.G. K.M. is a recipient of an INSERM 'contrat de jeunes chercheurs'. B.C. is a recipient of a grant from Fondation pour la Recherche Médicale (FRM). E.R.G. is supported in part by the Inserm Avenir Program. This work benefited from funding from the European Community's Seventh Framework Programme project OPTISTEM (Optimization of stem cell therapy for degenerative epithelial and muscle diseases contract number Health-F5-2009-223098). The Myology Group is the beneficiary of a Strategic Plan Support from the Association Française contre les Myopathies (AFM) and is affiliated with the Institute of Myology/ Association Institut Myologie.

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  1. Giovanna Marazzi and David A. Sassoon: Co-senior authors.

Authors and Affiliations

  1. Myology Group, UMR S 787 INSERM, Université Pierre et Marie Curie Paris VI, Paris, 75634, France

    Kathryn J. Mitchell, Alice Pannérec, Bruno Cadot, Ara Parlakian, Vanessa Besson, Edgar R. Gomes, Giovanna Marazzi & David A. Sassoon

  2. Myology Group, Stem Cell and Muscle Biology, UMR S 787 INSERM, Université Pierre et Marie Curie Paris VI, Paris, 75634, France

    Kathryn J. Mitchell, Alice Pannérec, Ara Parlakian, Vanessa Besson, Giovanna Marazzi & David A. Sassoon

  3. Myology Group, Cytoskeleton Architecture and Cell Polarization, UMR S 787 INSERM, Université Pierre et Marie Curie Paris VI, Paris, 75634, France

    Bruno Cadot & Edgar R. Gomes

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Contributions

All authors designed research; K.J.M., A.P., B.C., A.P. and V.B. performed research; B.C., V.B. and E.R.G. contributed new reagents/analytic tools; all authors analysed data and K.J.M., G.M. and D.A.S. wrote the paper.

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Correspondence to David A. Sassoon.

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Mitchell, K., Pannérec, A., Cadot, B. et al. Identification and characterization of a non-satellite cell muscle resident progenitor during postnatal development. Nat Cell Biol 12, 257–266 (2010). https://doi.org/10.1038/ncb2025

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