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Satellite cells, the engines of muscle repair

Nature Reviews Molecular Cell Biology volume 13, pages 127–133 (2012)Cite this article

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Abstract

Satellite cells are a heterogeneous population of stem and progenitor cells that are required for the growth, maintenance and regeneration of skeletal muscle. The transcription factors paired-box 3 (PAX3) and PAX7 have essential and overlapping roles in myogenesis. PAX3 acts to specify embryonic muscle precursors, whereas PAX7 enforces the satellite cell myogenic programme while maintaining the undifferentiated state. Recent experiments have suggested that PAX7 is dispensable in adult satellite cells. However, these findings are controversial, and the issue remains unresolved.

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Figure 1: Satellite cell fate in regeneration.
Figure 2: Schematic of satellite stem cell fate in self-renewal.
Figure 3: Schematic of the cell interactions during regeneration.

References

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  3. Schultz, E., Gibson, M. C. & Champion, T. Satellite cells are mitotically quiescent in mature mouse muscle: an EM and radioautographic study. J. Exp. Zool. 206, 451–456 (1978).

    CAS  PubMed  Google Scholar 

  4. Bentzinger, C. F., von Maltzahn, J. & Rudnicki, M. A. Extrinsic regulation of satellite cell specification. Stem Cell Res. Ther. 1, 27 (2010).

    PubMed  PubMed Central  Google Scholar 

  5. Braun, T. & Gautel, M. Transcriptional mechanisms regulating skeletal muscle differentiation, growth and homeostasis. Nature Rev. Mol. Cell Biol. 12, 349–361 (2011).

    CAS  Google Scholar 

  6. Buckingham, M. & Vincent, S. D. Distinct and dynamic myogenic populations in the vertebrate embryo. Curr. Opin. Genet. Dev. 19, 444–453 (2009).

    CAS  PubMed  Google Scholar 

  7. Punch, V. G., Jones, A. E. & Rudnicki, M. A. Transcriptional networks that regulate muscle stem cell function. Wiley Interdiscip. Rev. Syst. Biol. Med. 1, 128–140 (2009).

    CAS  PubMed  Google Scholar 

  8. Rudnicki, M. A., Braun, T., Hinuma, S. & Jaenisch, R. Inactivation of MyoD in mice leads to up-regulation of the myogenic HLH gene Myf-5 and results in apparently normal muscle development. Cell 71, 383–390 (1992).

    CAS  PubMed  Google Scholar 

  9. Braun, T., Rudnicki, M. A., Arnold, H. H. & Jaenisch, R. Targeted inactivation of the muscle regulatory gene Myf-5 results in abnormal rib development and perinatal death. Cell 71, 369–382 (1992).

    CAS  PubMed  Google Scholar 

  10. Kaul, A., Köster, M., Neuhaus, H. & Braun, T. Myf-5 revisited: loss of early myotome formation does not lead to a rib phenotype in homozygous Myf-5 mutant mice. Cell 102, 17–19 (2000).

    CAS  PubMed  Google Scholar 

  11. Rudnicki, M. A. et al. MyoD or Myf-5 is required for the formation of skeletal muscle. Cell 75, 1351–1359 (1993).

    CAS  PubMed  Google Scholar 

  12. Kassar-Duchossoy, L. et al. Mrf4 determines skeletal muscle identity in Myf5:Myod double-mutant mice. Nature 431, 466–471 (2004).

    CAS  PubMed  Google Scholar 

  13. Hasty, P. et al. Muscle deficiency and neonatal death in mice with a targeted mutation in the myogenin gene. Nature 364, 501–506 (1993).

    CAS  PubMed  Google Scholar 

  14. Nabeshima, Y. et al. Myogenin gene disruption results in perinatal lethality because of severe muscle defect. Nature 364, 532–535 (1993).

    CAS  PubMed  Google Scholar 

  15. Rawls, A. et al. Overlapping functions of the myogenic bHLH genes MRF4 and MyoD revealed in double mutant mice. Development 125, 2349–2358 (1998).

    CAS  PubMed  Google Scholar 

  16. Hu, P., Geles, K. G., Paik, J.-H., DePinho, R. A. & Tjian, R. Codependent activators direct myoblast specific MyoD transcription. Dev. Cell 15, 534–546 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Bajard, L. et al. A novel genetic hierarchy functions during hypaxial myogenesis: Pax3 directly activates Myf5 in muscle progenitor cells in the limb. Genes Dev. 20, 2450–2464 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. McKinnell, I. W. et al. Pax7 activates myogenic genes by recruitment of a histone methyltransferase complex. Nature Cell Biol. 10, 77–84 (2008).

    CAS  PubMed  Google Scholar 

  19. Darabi, R. et al. Assessment of the myogenic stem cell compartment following transplantation of Pax3/Pax7- induced embryonic stem cell-derived progenitors. Stem Cells 29, 777–790 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Schäfer, B. W., Czerny, T., Bernasconi, M., Genini, M. & Busslinger, M. Molecular cloning and characterization of a human PAX-7 cDNA expressed in normal and neoplastic myocytes. Nucleic Acids Res. 22, 4574–4582 (1994).

    PubMed  PubMed Central  Google Scholar 

  21. Bober, E., Franz, T., Arnold, H. H., Gruss, P. & Tremblay, P. Pax-3 is required for the development of limb muscles: a possible role for the migration of dermomyotomal muscle progenitor cells. Development 120, 603–612 (1994).

    CAS  PubMed  Google Scholar 

  22. Borycki, A. G., Li, J., Jin, F., Emerson, C. P. & Epstein, J. A. Pax3 functions in cell survival and in pax7 regulation. Development 126, 1665–1674 (1999).

    CAS  PubMed  Google Scholar 

  23. Tajbakhsh, S., Rocancourt, D., Cossu, G. & Buckingham, M. Redefining the genetic hierarchies controlling skeletal myogenesis: Pax-3 and Myf-5 act upstream of MyoD. Cell 89, 127–138 (1997).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  25. Relaix, F., Rocancourt, D., Mansouri, A. & Buckingham, M. Divergent functions of murine Pax3 and Pax7 in limb muscle development. Genes Dev. 18, 1088–1105 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Kassar-Duchossoy, L. et al. Pax3/Pax7 mark a novel population of primitive myogenic cells during development. Genes Dev. 19, 1426–1431 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Hutcheson, D. A., Zhao, J., Merrell, A., Haldar, M. & Kardon, G. Embryonic and fetal limb myogenic cells are derived from developmentally distinct progenitors and have different requirements for β-catenin. Genes Dev. 23, 997–1013 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Boutet, S. C., Disatnik, M.-H., Chan, L. S., Iori, K. & Rando, T. A. Regulation of Pax3 by proteasomal degradation of monoubiquitinated protein in skeletal muscle progenitors. Cell 130, 349–362 (2007).

    CAS  PubMed  Google Scholar 

  31. Kuang, S., Chargé, S. B., Seale, P., Huh, M. & Rudnicki, M. A. Distinct roles for Pax7 and Pax3 in adult regenerative myogenesis. J. Cell Biol. 172, 103–113 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Conboy, I. M. & Rando, T. A. The regulation of Notch signaling controls satellite cell activation and cell fate determination in postnatal myogenesis. Dev. Cell 3, 397–409 (2002).

    CAS  PubMed  Google Scholar 

  34. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Lepper, C., Conway, S. J. & Fan, C.-M. Adult satellite cells and embryonic muscle progenitors have distinct genetic requirements. Nature 460, 627–631 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Olguin, H. C., Yang, Z., Tapscott, S. J. & Olwin, B. B. Reciprocal inhibition between Pax7 and muscle regulatory factors modulates myogenic cell fate determination. J. Cell Biol. 177, 769–779 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. White, R., Bierinx, A.-S., Gnocchi, V. & Zammit, P. Dynamics of muscle fibre growth during postnatal mouse development. BMC Dev. Biol. 10, 21 (2010).

    PubMed  PubMed Central  Google Scholar 

  38. Bischoff, R. in Myogenesis (eds Engel, A. G. & Franszini-Armstrong, C.) 97–118 (McGraw-Hill, New York,1994).

    Google Scholar 

  39. Fukada, S. et al. Hesr1 and Hesr3 are essential to generate undifferentiated quiescent satellite cells and to maintain satellite cell numbers. Development 138, 4609–4619 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Bjornson, C. R. R. et al. Notch signaling is necessary to maintain quiescence in adult muscle stem cells. Stem Cells 1 Nov 2011 (doi:10.1002/stem.773).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Mourikis, P. et al. A critical requirement for Notch signaling in maintenance of the quiescent skeletal muscle stem cell state. Stem Cells 8 Nov 2011 (doi:10.1002/stem.775).

    CAS  PubMed  Google Scholar 

  42. Kuang, S. & Rudnicki, M. A. The emerging biology of satellite cells and their therapeutic potential. Trends Mol. Med. 14, 82–91 (2008).

    CAS  PubMed  Google Scholar 

  43. Bosnakovski, D. et al. Prospective isolation of skeletal muscle stem cells with a Pax7 reporter. Stem Cells 26, 3194–3204 (2008).

    CAS  PubMed  PubMed Central  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).

    CAS  PubMed  Google Scholar 

  45. Schultz, E. Satellite cell proliferative compartments in growing skeletal muscles. Dev. Biol. 175, 84–94 (1996).

    CAS  PubMed  Google Scholar 

  46. 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).

    CAS  PubMed  Google Scholar 

  47. Yamashita, Y. M. Cell adhesion in regulation of asymmetric stem cell division. Curr. Opin. Cell Biol. 22, 605–610 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Le Grand, F., Jones, A. E., Seale, V., Scimè, A. & Rudnicki, M. A. Wnt7a activates the planar cell polarity pathway to drive the symmetric expansion of satellite stem cells. Cell Stem Cell 4, 535–547 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Yoshida, N., Yoshida, S., Koishi, K., Masuda, K. & Nabeshima, Y. Cell heterogeneity upon myogenic differentiation: down-regulation of MyoD and Myf-5 generates 'reserve cells'. J. Cell Sci. 111, 769–779 (1998).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Abou-Khalil, R. et al. Autocrine and paracrine angiopoietin 1/Tie-2 signaling promotes muscle satellite cell self-renewal. Cell Stem Cell 5, 298–309 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Shea, K. L. et al. Sprouty1 regulates reversible quiescence of a self-renewing adult muscle stem cell pool during regeneration. Cell Stem Cell 6, 117–129 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Lepper, C., Partridge, T. A. & Fan, C.-M. An absolute requirement for Pax7-positive satellite cells in acute injury-induced skeletal muscle regeneration. Development 138, 3639–3646 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Sambasivan, R. et al. Pax7-expressing satellite cells are indispensable for adult skeletal muscle regeneration. Development 138, 3647–3656 (2011).

    CAS  PubMed  Google Scholar 

  55. Murphy, M. M., Lawson, J. A., Mathew, S. J., Hutcheson, D. A. & Kardon, G. Satellite cells, connective tissue fibroblasts and their interactions are crucial for muscle regeneration. Development 138, 3625–3637 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Jejurikar, S. S. & Kuzon, W. M. Jr. Satellite cell depletion in degenerative skeletal muscle. Apoptosis 8, 573–578 (2003).

    CAS  PubMed  Google Scholar 

  57. Megeney, L. A., Kablar, B., Garrett, K., Anderson, J. E. & Rudnicki, M. A. MyoD is required for myogenic stem cell function in adult skeletal muscle. Genes Dev. 10, 1173–1183 (1996).

    CAS  PubMed  Google Scholar 

  58. Sacco, A. et al. Short telomeres and stem cell exhaustion model Duchenne muscular dystrophy in mdx/mTR mice. Cell 143, 1059–1071 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Palacios, D. et al. TNF/p38α/polycomb signaling to Pax7 locus in satellite cells links inflammation to the epigenetic control of muscle regeneration. Cell Stem Cell 7, 455–469 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Joe, A. W. B. et al. Muscle injury activates resident fibro/adipogenic progenitors that facilitate myogenesis. Nature Cell Biol. 12, 153–163 (2010).

    CAS  PubMed  Google Scholar 

  61. 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. Nature Cell Biol. 12, 143–152 (2010).

    CAS  PubMed  Google Scholar 

  62. Salleo, A., La Spada, G., Falzea, G., Denaro, M. G. & Cicciarello, R. Response of satellite cells and muscle fibers to long-term compensatory hypertrophy. J. Submicrosc. Cytol. 15, 929–940 (1983).

    CAS  PubMed  Google Scholar 

  63. Rosenblatt, J. D. & Parry, D. J. Gamma irradiation prevents compensatory hypertrophy of overloaded mouse extensor digitorum longus muscle. J. Appl. Physiol. 73, 2538–2543 (1992).

    CAS  PubMed  Google Scholar 

  64. McCarthy, J. J. & Esser, K. A. Counterpoint: satellite cell addition is not obligatory for skeletal muscle hypertrophy. J. Appl. Physiol. 103, 1100–1102 (2007).

    PubMed  Google Scholar 

  65. McCarthy, J. J. et al. Effective fiber hypertrophy in satellite cell-depleted skeletal muscle. Development 138, 3657–3666 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Gilbert, P. M. et al. Substrate elasticity regulates skeletal muscle stem cell self-renewal in culture. Science 329, 1078–1081 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Williams, B. A. & Ordahl, C. P. Pax-3 expression in segmental mesoderm marks early stages in myogenic cell specification. Development 120, 785–796 (1994).

    CAS  PubMed  Google Scholar 

  68. Lagha, M. et al. Pax3:Foxc2 reciprocal repression in the somite modulates muscular versus vascular cell fate choice in multipotent progenitors. Dev. Cell 17, 892–899 (2009).

    CAS  PubMed  Google Scholar 

  69. Aoyama, H. & Asamoto, K. Determination of somite cells: independence of cell differentiation and morphogenesis. Development 104, 15–28 (1988).

    CAS  PubMed  Google Scholar 

  70. Borycki, A. G., Mendham, L. & Emerson, C. P. Jr. Control of somite patterning by Sonic hedgehog and its downstream signal response genes. Development 125, 777–790 (1998).

    CAS  PubMed  Google Scholar 

  71. Tajbakhsh, S. et al. Differential activation of Myf5 and MyoD by different Wnts in explants of mouse paraxial mesoderm and the later activation of myogenesis in the absence of Myf5. Development 125, 4155–4162 (1998).

    CAS  PubMed  Google Scholar 

  72. Rios, A. C., Serralbo, O., Salgado, D. & Marcelle, C. Neural crest regulates myogenesis through the transient activation of NOTCH. Nature 473, 532–535 (2011).

    CAS  PubMed  Google Scholar 

  73. Heymann, S., Koudrova, M., Arnold, H., Köster, M. & Braun, T. Regulation and function of SF/HGF during migration of limb muscle precursor cells in chicken. Dev. Biol. 180, 566–578 (1996).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  75. Dellavalle, A. et al. Pericytes resident in postnatal skeletal muscle differentiate into muscle fibres and generate satellite cells. Nature Commun. 2, 499 (2011).

    CAS  Google Scholar 

  76. Sampaolesi, M. et al. Mesoangioblast stem cells ameliorate muscle function in dystrophic dogs. Nature 444, 574–579 (2006).

    CAS  PubMed  Google Scholar 

  77. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Tanaka, K. K. et al. Syndecan-4-expressing muscle progenitor cells in the SP engraft as satellite cells during muscle regeneration. Cell Stem Cell 4, 217–225 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Seale, P., Ishibashi, J., Scimè, 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).

    PubMed  PubMed Central  Google Scholar 

  80. Xynos, A. et al. Bone marrow-derived hematopoietic cells undergo myogenic differentiation following a Pax-7 independent pathway. Stem Cells 28, 965–973 (2010).

    CAS  PubMed  Google Scholar 

  81. Mitchell, K. J. et al. Identification and characterization of a non-satellite cell muscle resident progenitor during postnatal development. Nature Cell Biol. 12, 257–266 (2010).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank F. Bentzinger and H. Yin for critical reading of the manuscript. Y.X.W. is supported by a fellowship from the Ontario Research Fund and by the Canadian Institutes of Health Research (CIHR) Training Program in Regenerative Medicine. M.A.R. holds the Canada Research Chair in Molecular Genetics and is an International Research Scholar of the Howard Hughes Medical Institute. The work from the laboratory of M.A.R. is supported by grants from the US National Institutes of Health, the Howard Hughes Medical Institute, the CIHR, the Muscular Dystrophy Association and the Canada Research Chair Program.

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  1. Yu Xin Wang and Michael A. Rudnicki are at the Sprott Centre for Stem Cell Research, Ottawa Hospital Research Institute Ottawa, 501 Smyth Road Ottawa, Ontario K1H 8L6, Canada.,

    Yu Xin Wang & Michael A. Rudnicki

  2. Department of Cellular and Molecular Medicine, Yu Xin Wang and Michael A. Rudnicki are also at the Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.,

    Yu Xin Wang & Michael A. Rudnicki

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Wang, Y., Rudnicki, M. Satellite cells, the engines of muscle repair. Nat Rev Mol Cell Biol 13, 127–133 (2012). https://doi.org/10.1038/nrm3265

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