We document anatomic, molecular and developmental relationships between endothelial and myogenic cells within human skeletal muscle. Cells coexpressing myogenic and endothelial cell markers (CD56, CD34, CD144) were identified by immunohistochemistry and flow cytometry. These myoendothelial cells regenerate myofibers in the injured skeletal muscle of severe combined immunodeficiency mice more effectively than CD56+ myogenic progenitors. They proliferate long term, retain a normal karyotype, are not tumorigenic and survive better under oxidative stress than CD56+ myogenic cells. Clonally derived myoendothelial cells differentiate into myogenic, osteogenic and chondrogenic cells in culture. Myoendothelial cells are amenable to biotechnological handling, including purification by flow cytometry and long-term expansion in vitro, and may have potential for the treatment of human muscle disease.
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Bischoff, R. Proliferation of muscle satellite cells on intact myofibers in culture. Dev. Biol. 115, 129–139 (1986).
Bischoff, R. The satellite cell and muscle regeneration. In Myology: Basic and Clinical (Engel, A., Franzini-Armstrong, C. & Fischman D.A., eds.), 97–118, (McGraw-Hill, New York, 1994).
Skuk, D. & Tremblay, J.P. Myoblast transplantation: the current status of a potential therapeutic tool for myopathies. J. Muscle Res. Cell Motil. 24, 285–300 (2003).
Partridge, T.A. Invited review: myoblast transfer: a possible therapy for inherited myopathies? Muscle Nerve 14, 197–212 (1991).
Menasche, P. et al. Myoblast transplantation for heart failure. Lancet 357, 279–280 (2001).
Cao, B., Deasy, B.M., Pollett, J. & Huard, J. Cell therapy for muscle regeneration and repair. Phys. Med. Rehabil. Clin. N. Am. 16, 889–907, viii (2005).
Menasche, P. Cellular transplantation: hurdles remaining before widespread clinical use. Curr. Opin. Cardiol. 19, 154–161 (2004).
Miller, J.B., Schaefer, L. & Dominov, J.A. Seeking muscle stem cells. Curr. Top. Dev. Biol. 43, 191–219 (1999).
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).
Gussoni, E. et al. Dystrophin expression in the mdx mouse restored by stem cell transplantation. Nature 401, 390–394 (1999).
Partridge, T.A. Stem cell therapies for neuromuscular diseases. Acta Neurol. Belg. 104, 141–147 (2004).
Peault, B. et al. Stem and progenitor cells in skeletal muscle development, maintenance, and therapy. Mol. Ther. 15, 867–877 (2007).
Oshima, H. et al. Differential myocardial infarct repair with muscle stem cells compared to myoblasts. Mol. Ther. 12, 1130–1141 (2005).
Payne, T.R. et al. Regeneration of dystrophin-expressing myocytes in the mdx heart by skeletal muscle stem cells. Gene Ther. 12, 1264–1274 (2005).
Deasy, B.M. et al. Long-term self-renewal of postnatal muscle-derived stem cells. Mol. Biol. Cell 16, 3323–3333 (2005).
Deasy, B.M. et al. A role for cell sex in stem cell-mediated skeletal muscle regeneration: female cells have higher muscle regeneration efficiency. J. Cell Biol. 177, 73–86 (2007).
Mueller, G.M., O'Day, T., Watchko, J.F. & Ontell, M. Effect of injecting primary myoblasts versus putative muscle-derived stem cells on mass and force generation in mdx mice. Hum. Gene Ther. 13, 1081–1090 (2002).
Jankowski, R.J., Deasy, B.M., Cao, B., Gates, C. & Huard, J. The role of CD34 expression and cellular fusion in the regeneration capacity of myogenic progenitor cells. J. Cell Sci. 115, 4361–4374 (2002).
Jankowski, R.J. & Huard, J. Myogenic cellular transplantation and regeneration: sorting through progenitor heterogeneity. Panminerva Med. 46, 81–91 (2004).
Cao, B. et al. Muscle stem cells differentiate into haematopoietic lineages but retain myogenic potential. Nat. Cell Biol. 5, 640–646 (2003).
Wright, V. et al. BMP4-expressing muscle-derived stem cells differentiate into osteogenic lineage and improve bone healing in immunocompetent mice. Mol. Ther. 6, 169–178 (2002).
Kuroda, R. et al. Cartilage repair using bone morphogenetic protein 4 and muscle-derived stem cells. Arthritis Rheum. 54, 433–442 (2006).
Winitsky, S.O. et al. Adult murine skeletal muscle contains cells that can differentiate into beating cardiomyocytes in vitro. PLoS Biol. 3, e87 (2005).
Sarig, R., Baruchi, Z., Fuchs, O., Nudel, U. & Yaffe, D. Regeneration and transdifferentiation potential of muscle-derived stem cells propagated as myospheres. Stem Cells 24, 1769–1778 (2006).
Nomura, T. et al. Skeletal myosphere-derived progenitor cell transplantation promotes neovascularization in delta-sarcoglycan knockdown cardiomyopathy. Biochem. Biophys. Res. Commun. 352, 668–674 (2007).
Beresford, J.N., Bennett, J.H., Devlin, C., Leboy, P.S. & Owen, M.E. Evidence for an inverse relationship between the differentiation of adipocytic and osteogenic cells in rat marrow stromal cell cultures. J. Cell Sci. 102, 341–351 (1992).
Pittenger, M.F. et al. Multilineage potential of adult human mesenchymal stem cells. Science 284, 143–147 (1999).
Toma, C., Pittenger, M.F., Cahill, K.S., Byrne, B.J. & Kessler, P.D. Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart. Circulation 105, 93–98 (2002).
Prockop, D.J. Marrow stromal cells as stem cells for nonhematopoietic tissues. Science 276, 71–74 (1997).
Petersen, B.E. et al. Bone marrow as a potential source of hepatic oval cells. Science 284, 1168–1170 (1999).
Theise, N.D. et al. Derivation of hepatocytes from bone marrow cells in mice after radiation-induced myeloablation. Hepatology 31, 235–240 (2000).
Krause, D.S. et al. Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell 105, 369–377 (2001).
Mezey, E., Chandross, K.J., Harta, G., Maki, R.A. & McKercher, S.R. Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow. Science 290, 1779–1782 (2000).
Jiang, Y. et al. Multipotent progenitor cells can be isolated from postnatal murine bone marrow, muscle, and brain. Exp. Hematol. 30, 896–904 (2002).
Seaberg, R.M. et al. Clonal identification of multipotent precursors from adult mouse pancreas that generate neural and pancreatic lineages. Nat. Biotechnol. 22, 1115–1124 (2004).
Toma, J.G. et al. Isolation of multipotent adult stem cells from the dermis of mammalian skin. Nat. Cell Biol. 3, 778–784 (2001).
Wang, H.S. et al. Mesenchymal stem cells in the Wharton's jelly of the human umbilical cord. Stem Cells 22, 1330–1337 (2004).
Mitchell, K.E. et al. Matrix cells from Wharton's jelly form neurons and glia. Stem Cells 21, 50–60 (2003).
Shih, D.T. et al. Isolation and characterization of neurogenic mesenchymal stem cells in human scalp tissue. Stem Cells 23, 1012–1020 (2005).
Zuk, P.A. et al. Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng. 7, 211–228 (2001).
Barry, F.P. & Murphy, J.M. Mesenchymal stem cells: clinical applications and biological characterization. Int. J. Biochem. Cell Biol. 36, 568–584 (2004).
Seale, P. et al. Pax7 is required for the specification of myogenic satellite cells. Cell 102, 777–786 (2000).
Kumaravelu, P. et al. Quantitative developmental anatomy of definitive haematopoietic stem cells/long-term repopulating units (HSC/RUs): role of the aorta-gonad-mesonephros (AGM) region and the yolk sac in colonisation of the mouse embryonic liver. Development 129, 4891–4899 (2002).
Jaffredo, T., Gautier, R., Eichmann, A. & Dieterlen-Lievre, F. Intraaortic hemopoietic cells are derived from endothelial cells during ontogeny. Development 125, 4575–4583 (1998).
Nishikawa, S.I. et al. In vitro generation of lymphohematopoietic cells from endothelial cells purified from murine embryos. Immunity 8, 761–769 (1998).
North, T.E. et al. Runx1 expression marks long-term repopulating hematopoietic stem cells in the midgestation mouse embryo. Immunity 16, 661–672 (2002).
Oberlin, E., Tavian, M., Blazsek, I. & Peault, B. Blood-forming potential of vascular endothelium in the human embryo. Development 129, 4147–4157 (2002).
Kardon, G., Campbell, J.K. & Tabin, C.J. Local extrinsic signals determine muscle and endothelial cell fate and patterning in the vertebrate limb. Dev. Cell 3, 533–545 (2002).
Tamaki, T. et al. Identification of myogenic-endothelial progenitor cells in the interstitial spaces of skeletal muscle. J. Cell Biol. 157, 571–577 (2002).
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).
Cossu, G. & Bianco, P. Mesoangioblasts–vascular progenitors for extravascular mesodermal tissues. Curr. Opin. Genet. Dev. 13, 537–542 (2003).
Christov, C. et al. Muscle satellite cells and endothelial cells: close neighbors and privileged partners. Mol. Biol. Cell 18, 1397–1409 (2007).
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).
Sampaolesi, M. et al. Cell therapy of alpha-sarcoglycan null dystrophic mice through intra-arterial delivery of mesoangioblasts. Science 301, 487–492 (2003).
Galli, D. et al. Mesoangioblasts, vessel-associated multipotent stem cells, repair the infarcted heart by multiple cellular mechanisms: a comparison with bone marrow progenitors, fibroblasts, and endothelial cells. Arterioscler. Thromb. Vasc. Biol. 25, 692–697 (2005).
Sampaolesi, M. et al. Mesoangioblast stem cells ameliorate muscle function in dystrophic dogs. Nature 444, 574–579 (2006).
Zheng, B., Cao, B., Li, G. & Huard, J. Mouse adipose-derived stem cells undergo multilineage differentiation in vitro but primarily osteogenic and chondrogenic differentiation in vivo. Tissue Eng. 12, 1891–1901 (2006).
This work was supported in part by grants to J.H. from the Muscular Dystrophy Association (USA), the US National Institutes of Health (R01-AR049684; RO1-DE13420-06; IU54AR050733-01), the William F. and Jean W. Donaldson Chair, the Orris C. Hirtzel and Beatrice Dewey Hirtzel Memorial Foundation at Children's Hospital of Pittsburgh, the Henry J. Mankin Endowed Chair at the University of Pittsburgh and the Lemieux Foundation at the University of Pittsburgh. The authors wish to thank S.C. Watkins for his assistance with confocal microscopy, A. Usas and J.A. Jadlowiec for help with tumorigenesis experiments in vivo, J. Tebbets and M. Branca for technical help with cryostat sectioning, and David Humiston for editorial assistance.
The authors declare no competing financial interests.
Supplementary Tables 1–5; Supplementary Figures 1,2 (PDF 270 kb)
Video of Figure 1f. Nuclei were stained blue with Dapi (× 1000). (AVI 39938 kb)
Video of Figure 1g. CD56 (red) and UEA-1 (green) co-staining. Nuclei were stained blue with Dapi (× 1000). (AVI 89091 kb)
Video of Figure 1h. CD56 (red) and VE-cad (green) co-staining. Nuclei were stained blue with Dapi (× 1000). (AVI 89091 kb)
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Zheng, B., Cao, B., Crisan, M. et al. Prospective identification of myogenic endothelial cells in human skeletal muscle. Nat Biotechnol 25, 1025–1034 (2007). https://doi.org/10.1038/nbt1334