Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Pericytes of human skeletal muscle are myogenic precursors distinct from satellite cells

Nature Cell Biology volume 9, pages 255–267 (2007)Cite this article

Abstract

Cells derived from blood vessels of human skeletal muscle can regenerate skeletal muscle, similarly to embryonic mesoangioblasts. However, adult cells do not express endothelial markers, but instead express markers of pericytes, such as NG2 proteoglycan and alkaline phosphatase (ALP), and can be prospectively isolated from freshly dissociated ALP+ cells. Unlike canonical myogenic precursors (satellite cells), pericyte-derived cells express myogenic markers only in differentiated myotubes, which they form spontaneously with high efficiency. When transplanted into severe combined immune deficient–X-linked, mouse muscular dystrophy (scid–mdx) mice, pericyte-derived cells colonize host muscle and generate numerous fibres expressing human dystrophin. Similar cells isolated from Duchenne patients, and engineered to express human mini-dystrophin, also give rise to many dystrophin-positive fibres in vivo. These data show that myogenic precursors, distinct from satellite cells, are associated with microvascular walls in the human skeletal muscle, may represent a correlate of embryonic 'mesoangioblasts' present after birth and may be a promising candidate for future cell-therapy protocols in patients.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: In vitro characterization of human adult interstitial cells.
Figure 2: Phenotype of human adult pericyte-derived cells.
Figure 3: ALP activity in interstitial cells and muscle tissue.
Figure 4: Clonal analysis of cells isolated from muscle.
Figure 5: In vitro myogenic differentiation of human pericyte derived cells.
Figure 6: Time course of myogenic differentiation in cultures of pericyte-derived cells and satellite cell-derived myogenic precursors.
Figure 7: Tissue distribution of human pericyte-derived cells in dystrophic muscle.
Figure 8: Immunofluorescence microscopy and western blot analysis of scid–mdx mouse tibialis anterior, after three serial transplantations of 5 × 105human normal pericyte-derived cells and stained with antibodies against laminin (green) and human dystrophin (Dys1/Dys2 or Dys3, red).

Similar content being viewed by others

References

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  3. 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 

  4. Morgan, J. E. et al. Long-term persistence and migration of myogenic cells injected into pre-irradiated muscles of mdx mice. J. Neurol. Sci. 115, 191–200 (1993).

    Article  CAS  Google Scholar 

  5. Beauchamp, J. R., Morgan, J. E., Pagel, C. N. & Partridge, T. A. Dynamics of myoblast transplantation reveal a discrete minority of precursors with stem cell-like properties as the myogenic source. J. Cell Biol. 144, 1113–1121 (1999).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  7. Cossu, G. & Sampaolesi, M. New therapies for muscular dystrophy: cautious optimism? Trends Mol. Med. 10, 516–520 (2004).

    Article  CAS  Google Scholar 

  8. Minasi, M. G. et al. The meso-angioblast: a multipotent, self-renewing cell that originates from the dorsal aorta and differentiates into most mesodermal tissues. Development 129, 2773–2783 (2002).

    CAS  PubMed  Google Scholar 

  9. Sampaolesi, M. et al. Cell therapy of α sarcoglycan null dystrophic mice through intra-arterial delivery of mesoangioblasts. Science 301, 487–492 (2003).

    Article  CAS  Google Scholar 

  10. Armulik, A., Abramsson, A. & Betsholtz, C. Endothelial/pericyte interaction. Circ. Res. 97, 512–523 (2005).

    Article  CAS  Google Scholar 

  11. Safadi, A., Livne, E., Silbermann, M. & Reznick, A. Z. Activity of alkaline phosphatase in rat skeletal muscle localized along the sarcolemma and endothelial cell membranes. J. Histochem. Cytochem. 39, 199–203 (1991).

    Article  CAS  Google Scholar 

  12. Katagiri, T. et al. Bone morphogenetic protein-2 converts the differentiation pathway of C2C12 myoblasts into the osteoblast lineage. J. Cell Biol. 127, 1756–1766 (1994).

    Article  Google Scholar 

  13. Galvez, B. G. et al. Complete repair of dystrophic skeletal muscle by mesoangioblasts with enhanced homing ability. J. Cell Biol. 174, 231–243 (2006).

    Article  CAS  Google Scholar 

  14. Cossu, G. & Bianco, P. Mesoangioblasts, vascular precursors for extra-vascular mesoderm. Curr. Opin. Genet. Develop. 13, 537–542 (2003).

    Article  CAS  Google Scholar 

  15. Neumeyer, A. M. et al. Arterial delivery of myoblasts to skeletal muscle Neurology 42, 2258–2262 (1992).

    Article  CAS  Google Scholar 

  16. Bianco, P. & Gehron Robey, P. Marrow stromal stem cells. J. Clin. Invest. 105, 1663–1668 (2000).

    Article  CAS  Google Scholar 

  17. Wakitani, S., Saito, T. & Caplan, A. I. Myogenic cells derived from rat bone marrow mesenchymal stem cells exposed to 5-azacytidine. Muscle Nerve 12, 1417–1426 (1995).

    Article  Google Scholar 

  18. Asahara, T. et al. Isolation of putative precursor endothelial cells for angiogenesis. Science 275, 964–967 (1997).

    Article  CAS  Google Scholar 

  19. Reyes, M. et al. Purification and ex vivo expansion of postnatal human marrow mesodermal precursor cells. Blood 98, 2615–2625 (2001).

    Article  CAS  Google Scholar 

  20. Qu-Petersen, Z. et al. Identification of a novel population of muscle stem cells in mice: potential for muscle regeneration J. Cell Biol. 157, 851–864 (2002).

    Article  CAS  Google Scholar 

  21. 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 

  22. 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 

  23. Bachrach, E. et al. Systemic delivery of human mini-dystrophin to regenerating mouse dystrophic muscle by muscle precursor cells. Proc. Natl Acad. Sci. USA 101, 3581–3586 (2004).

    Article  CAS  Google Scholar 

  24. Torrente, Y., et al. Human circulating AC133+ stem cells replenish the satellite cell pool, restore dystrophin expression and ameliorate function upon transplantation in murine dystrophic skeletal muscle. J. Clin. Invest. 114, 182–195 (2004).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  26. De Bari, C. et al. Skeletal muscle repair by adult human mesenchymal stem cells from synovial membrane. J Cell Biol. 160, 909–918 (2003).

    Article  CAS  Google Scholar 

  27. Toma, J. G. et al. Isolation of multipotent adult stem cells from the dermis of mammalian skin. Nature Cell. Biol. 3, 778–784 (2001).

    Article  CAS  Google Scholar 

  28. Rodriguez, A. M. et al. Transplantation of a multipotent cell population from human adipose tissue induces dystrophin expression in the immunocompetent mdx mouse. J. Exp. Med. 201, 1397–1405 (2005).

    Article  CAS  Google Scholar 

  29. Dezawa, M. et al. Bone marrow stromal cells generate muscle cells and repair muscle degeneration. Science 309, 314–317 (2005).

    Article  CAS  Google Scholar 

  30. Luo, D., Renault, V. M. & Rando, T. A. The regulation of Notch signaling in muscle stem cell activation and postnatal myogenesis. Semin. Cell. Dev. Biol. 16, 612–622 (2005).

    Article  CAS  Google Scholar 

  31. Leong, K. G. & Karsan, A. Recent insights into the role of Notch signaling in tumorigenesis. Blood 107, 2223–2233 (2005).

    Article  Google Scholar 

  32. Lattanzi, L. et al. High efficiency myogenic conversion of human fibroblasts by adenoviral vector-mediated MyoD gene transfer. J. Clin. Invest. 101, 2119–2128 (1998).

    Article  CAS  Google Scholar 

  33. Wright, W. E., Shay, J. W. & Piatyszek, M. A. Modifications of a telomeric repeat amplification protocol (TRAP) result in increased reliability, linearity and sensitivity. Nucleic Acids Res. 23, 3794–4005 (1995).

    Article  CAS  Google Scholar 

  34. Ouellette, M. M. et al. Subsenescent telomere lengths in fibroblasts immortalized by limiting amounts of telomerase. J. Biol. Chem. 275, 10072–10076 (2000).

    Article  CAS  Google Scholar 

  35. Li, S. et al. Stable transduction of myogenic cells with lentiviral vectors expressing a minidystrophin. Gene. Ther. 12, 1099–1108 (2005).

    Article  CAS  Google Scholar 

  36. Irizarry, R. A. et al. Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics 4, 249–264 (2003).

    Article  Google Scholar 

  37. Liu, W. M. et al. Analysis of high density expression microarrays with signed-rank call algorithms. Bioinformatics 18, 1593–1599 (2002).

    Article  CAS  Google Scholar 

  38. Tusher, V. G., Tibshirani, R. & Chu,G. Significance analysis of microarrays applied to the ionizing radiation response. Proc. Natl Acad. Sci. USA 98, 5116–5121 (2001).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from Muscular Dystrophy Association (MDA), Telethon, Association Française contra les Myopathies (AFM), Parent Project Onlus, Cassadi Risparmio Province Lombarde (CARIPLO), Associazione Italiana ricerca sul Cancro (AIRC), EC 'Eurostemcell', 'Cellsintoorgan', MyoAmp and 'Genostem', and the Italian Ministries of Health and Research. We thank G. Arrigo for help with karyotype analysis and A. Palini for help with FACS analysis. We also thank E. Dejana for advice and for reading the manuscript.

Author information

Author notes

  1. Arianna Dellavalle and Maurilio Sampaolesi: These authors contributed equally to this work.

Authors and Affiliations

  1. Stem Cell Research Institute, San Raffaele Scientific Institute, 58 Via Olgettina, Milan, 20132, Italy

    Arianna Dellavalle, Maurilio Sampaolesi, Rossana Tonlorenzi, Laura Perani, Anna Innocenzi, Beatriz G. Galvez, Graziella Messina, Giuseppe Peretti & Giulio Cossu

  2. Department of Experimental Medicine, University of Pavia, 6 Via Forlanini, Pavia, 27100, Italy

    Maurilio Sampaolesi

  3. Department of Biomedical Sciences, University of Modena and Reggio Emilia, 287 Via Campi, Modena, 41100, Italy

    Enrico Tagliafico & Stefano Ferrari

  4. Institute of Cell Biology and Tissue Engineering, San Raffaele Biomedical Science Park, 100/2 Via Castel Romano, Rome, 00128, Italy

    Benedetto Sacchetti, Paolo Bianco & Giulio Cossu

  5. Department of Cellular and Developmental Biology, University of Rome La Sapienza, 5 Piazza Aldo Moro, Rome, 00161, Italy

    Graziella Messina

  6. Department of Neurology, Catholic University, 8 Largo A. Gemelli, Rome, 00168, Italy

    Roberta Morosetti

  7. Department of Neurology, University of Washington, 1959 N.E. Pacific Street, Seattle, 98195-7720, WA, USA

    Sheng Li & Jeffrey S. Chamberlain

  8. Department of Neurological Science, Ospedale Maggiore Policlinico, University of Milan, 35 Via Francesco Sforza, Milan, 20122, Italy

    Marzia Belicchi & Yvan Torrente

  9. UT Southwestern Medical Center, Dallas, 5323 Harry Hines Blvd., Dallas, 75390-9039, TX, USA

    Woodring E. Wright

  10. Department of Experimental Pathology, University of Rome La Sapienza, 324 Via Regina Elena, Rome, 00161, Italy

    Paolo Bianco

  11. Department of Biology, University of Milan, 26 Via Celoria, Milan, 20130, Italy

    Giulio Cossu

Authors
  1. Arianna Dellavalle
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maurilio Sampaolesi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rossana Tonlorenzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Enrico Tagliafico
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Benedetto Sacchetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Laura Perani
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Anna Innocenzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Beatriz G. Galvez
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Graziella Messina
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Roberta Morosetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Sheng Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Marzia Belicchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Giuseppe Peretti
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Jeffrey S. Chamberlain
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Woodring E. Wright
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Yvan Torrente
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Stefano Ferrari
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Paolo Bianco
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Giulio Cossu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

A.D. and M.S. coordinated the work and performed the in vivo transplantation and functional tests. R.T. performed the cell cultures with help from G.M. and R.M. E.T. and S.F. conducted the microarray analysis. B.S. and A.D. did the FACS work. L.P. performed the PCR and western blot analysis. A.I. and M.B. did the immunocytochemistry. B.G.G. performed the homing experiment. S.L. and J.S.C. provided the viral vectors and advice. G.P. and Y.T. provided the biological samples. W.E.W. performed the telomerase work, provide advice and revised the manuscript. P.B. and G.C. coordinated the whole project and wrote the manuscript.

Corresponding authors

Correspondence to Paolo Bianco or Giulio Cossu.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary Figures S1, S2, S3 and Supplementary Methods (PDF 691 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dellavalle, A., Sampaolesi, M., Tonlorenzi, R. et al. Pericytes of human skeletal muscle are myogenic precursors distinct from satellite cells. Nat Cell Biol 9, 255–267 (2007). https://doi.org/10.1038/ncb1542

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb1542

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing