Abstract
Recent studies have shown that cells from the bone marrow can give rise to differentiated skeletal muscle fibers. However, the mechanisms and identities of the cell types involved have remained unknown, and the validity of the observation has been questioned. Here, we use transplantation of single CD45+ hematopoietic stem cells (HSCs) to demonstrate that the entire circulating myogenic activity in bone marrow is derived from HSCs and their hematopoietic progeny. We also show that ongoing muscle regeneration and inflammatory cell infiltration are required for HSC-derived contribution, which does not occur through a myogenic stem cell intermediate. Using a lineage tracing strategy, we show that myofibers are derived from mature myeloid cells in response to injury. Our results indicate that circulating myeloid cells, in response to inflammatory cues, migrate to regenerating skeletal muscle and stochastically incorporate into mature myofibers.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Clarke, D.L. et al. Generalized potential of adult neural stem cells. Science 288, 1660–1663 (2000).
Ferrari, G. et al. Muscle regeneration by bone marrow-derived myogenic progenitors. Science 279, 1528–1530 (1998).
Grant, M.B. et al. Adult hematopoietic stem cells provide functional hemangioblast activity during retinal neovascularization. Nat. Med. 8, 607–612 (2002).
Gussoni, E. et al. Dystrophin expression in the mdx mouse restored by stem cell transplantation. Nature 401, 390–394 (1999).
Jackson, K.A. et al. Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. J. Clin. Invest. 107, 1395–1402 (2001).
Lagasse, E. et al. Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nat. Med. 6, 1229–1234 (2000).
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).
Petersen, B.E. et al. Bone marrow as a potential source of hepatic oval cells. Science 284, 1168–1170 (1999).
Goodell, M.A. Stem cells: is there a future in plastics? Curr. Opin. Cell Biol. 13, 662–665 (2001).
Morshead, C.M., Benveniste, P., Iscove, N.N. & van der Kooy, D. Hematopoietic competence is a rare property of neural stem cells that may depend on genetic and epigenetic alterations. Nat. Med. 8, 268–273 (2002).
Castro, R.F. et al. Failure of bone marrow cells to transdifferentiate into neural cells in vivo. Science 297, 1299 (2002).
McKinney-Freeman, S.L. et al. Muscle-derived hematopoietic stem cells are hematopoietic in origin. Proc. Natl. Acad. Sci. USA 99, 1341–1346 (2002).
Vassilopoulos, G., Wang, P.R. & Russell, D.W. Transplanted bone marrow regenerates liver by cell fusion. Nature 422, 901–904 (2003).
Wang, X. et al. Cell fusion is the principal source of bone-marrow-derived hepatocytes. Nature 422, 897–901 (2003).
Fukada, S. et al. Muscle regeneration by reconstitution with bone marrow or fetal liver cells from green fluorescent protein-gene transgenic mice. J. Cell. Sci. 115, 1285–1293 (2002).
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).
Jiang, Y. et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 418, 41–49 (2002).
Corti, S. et al. A subpopulation of murine bone marrow cells fully differentiates along the myogenic pathway and participates in muscle repair in the mdx dystrophic mouse. Exp. Cell. Res. 277, 74–85 (2002).
Goodell, M.A. et al. Dye efflux studies suggest that hematopoietic stem cells expressing low or undetectable levels of CD34 antigen exist in multiple species. Nat. Med. 3, 1337–1345 (1997).
Spangrude, G.J., Heimfeld, S. & Weissman, I.L. Purification and characterization of mouse hematopoietic stem cells. Science 241, 58–62 (1988).
Wagers, A.J., Sherwood, R.I., Christensen, J.L. & Weissman, I.L. Little evidence for developmental plasticity of adult hematopoietic stem cells. Science 297, 2256–2259 (2002).
Osawa, M., Hanada, K., Hamada, H. & Nakauchi, H. Long-term lymphohematopoietic reconstitution by a single CD34-low/negative hematopoietic stem cell. Science 273, 242–245 (1996).
Goodell, M.A. Stem cell identification and sorting using the Hoechst 33342 Side Population (SP). in Current Protocols in Cytometry vol. 2 (eds. Robinson, J.P. et al.) 9.18.1–9.18.11 (Wiley, New York, 2002).
Kelly, R., Alonso, S., Tajbakhsh, S., Cossu, G. & Buckingham, M. Myosin light chain 3F regulatory sequences confer regionalized cardiac and skeletal muscle expression in transgenic mice. J. Cell Biol. 129, 383–396 (1995).
Ralston, E. & Hall, Z.W. Transfer of a protein encoded by a single nucleus to nearby nuclei in multinucleated myotubes. Science 244, 1066–1069 (1989).
Wakitani, S., Saito, T. & Caplan, A.I. Myogenic cells derived from rat bone marrow mesenchymal stem cells exposed to 5-azacytidine. Muscle Nerve 18, 1417–1426 (1995).
Jorgensen, C., Djouad, F., Apparailly, F. & Noel, D. Engineering mesenchymal stem cells for immunotherapy. Gene Ther. 10, 928–931 (2003).
De la Porte, S., Morin, S. & Koenig, J. Characteristics of skeletal muscle in mdx mutant mice. Int. Rev. Cytol. 191, 99–148 (1999).
Milner, D.J., Weitzer, G., Tran, D., Bradley, A. & Capetanaki, Y. Disruption of muscle architecture and myocardial degeneration in mice lacking desmin. J. Cell Biol. 134, 1255–1270 (1996).
Ferrari, G., Stornaiuolo, A. & Mavilio, F. Failure to correct murine muscular dystrophy. Nature 411, 1014–1015 (2001).
Orimo, S., Hiyamuta, E., Arahata, K. & Sugita, H. Analysis of inflammatory cells and complement C3 in bupivacaine-induced myonecrosis. Muscle Nerve 14, 515–520 (1991).
Parrish, E.P. et al. Targeting widespread sites of damage in dystrophic muscle: engrafted macrophages as potential shuttles. Gene Ther. 3, 13–20 (1996).
Clausen, B.E., Burkhardt, C., Reith, W., Renkawitz, R. & Forster, I. Conditional gene targeting in macrophages and granulocytes using LysMcre mice. Transgenic Res. 8, 265–277 (1999).
Cross, M., Mangelsdorf, I., Wedel, A. & Renkawitz, R. Mouse lysozyme M gene: isolation, characterization, and expression studies. Proc. Natl. Acad. Sci. USA 85, 6232–6236 (1988).
Soriano, P. Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat. Genet. 21, 70–71 (1999).
Schultz, E. & McCormick, K.M. Skeletal muscle satellite cells. Rev. Physiol. Biochem. Pharmacol. 123, 213–257 (1994).
Zambrowicz, B.P. et al. Disruption of overlapping transcripts in the ROSA β geo 26 gene trap strain leads to widespread expression of β-galactosidase in mouse embryos and hematopoietic cells. Proc. Natl. Acad. Sci. USA 94, 3789–3794 (1997).
Okabe, M., Ikawa, M., Kominami, K., Nakanishi, T. & Nishimune, Y. 'Green mice' as a source of ubiquitous green cells. FEBS Lett. 407, 313–319 (1997).
Wakeford, S., Watt, D.J. & Partridge, T.A. X-irradiation improves mdx mouse muscle as a model of myofiber loss in DMD. Muscle Nerve 14, 42–50 (1991).
Quinlan, J.G. et al. Radiation inhibition of mdx mouse muscle regeneration: dose and age factors. Muscle Nerve 18, 201–206 (1995).
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).
Kawada, H. & Ogawa, M. Bone marrow origin of hematopoietic progenitors and stem cells in murine muscle. Blood 98, 2008–2013 (2001).
McKinney-Freeman, S.L. et al. Altered phenotype and reduced function of muscle-derived hematopoietic stem cells. Exp. Hematol. 31, 806–814 (2003).
Khurana, T.S. & Davies, K.E. Pharmacological strategies for muscular dystrophy. Nat. Rev. Drug Discov. 2, 379–390 (2003).
De Luca, A., Pierno, S., Liantonio, A. & Conte Camerino, D. Pre-clinical trials in Duchenne dystrophy: what animal models can tell us about potential drug effectiveness. Neuromuscul. Disord. 12 (suppl. 1), S142–S146 (2002).
Wong, B.L. & Christopher, C. Corticosteroids in Duchenne muscular dystrophy: a reappraisal. J. Child Neurol. 17, 183–190 (2002).
Lescaudron, L. et al. Blood borne macrophages are essential for the triggering of muscle regeneration following muscle transplant. Neuromuscul. Disord. 9, 72–80 (1999).
Vignery, A. Osteoclasts and giant cells: macrophage-macrophage fusion mechanism. Int. J. Exp. Pathol. 81, 291–304 (2000).
Horsley, V., Jansen, K.M., Mills, S.T. & Pavlath, G.K. IL-4 acts as a myoblast recruitment factor during mammalian muscle growth. Cell 113, 483–494 (2003).
Alvarez-Dolado, M. et al. Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes. Nature advance online publication, 12 October 2003 (doi:10.1038/nature02069).
Goodell, M.A., Brose, K., Paradis, G., Conner, A.S. & Mulligan, R.C. Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J. Exp. Med. 183, 1797–1806 (1996).
Lu, Q.L. & Partridge, T.A. A new blocking method for application of murine monoclonal antibody to mouse tissue sections. J. Histochem. Cytochem. 46, 977–984 (1998).
Rando, T.A. & Blau, H.M. Primary mouse myoblast purification, characterization, and transplantation for cell-mediated gene therapy. J. Cell Biol. 125, 1275–1287 (1994).
Acknowledgements
F.D.C. was a fellow of the American Liver Foundation. M.A.G. is a Scholar of the Leukemia and Lymphoma Society. K.A.J. is a fellow of the Leukemia and Lymphoma Society and of the Muscular Dystrophy Association. This work was supported by grants to M.A.G. from the Muscular Dystrophy Association and the National Institutes of Health. We thank M. Cubbage for flow cytometry assistance, F. Mavilio (HSR-TIGET, Italy) for MLacZ mice, L. Pao (Harvard) for LysM-Cre mice, and D. Burton for animal care.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Rights and permissions
About this article
Cite this article
Camargo, F., Green, R., Capetenaki, Y. et al. Single hematopoietic stem cells generate skeletal muscle through myeloid intermediates. Nat Med 9, 1520–1527 (2003). https://doi.org/10.1038/nm963
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nm963
This article is cited by
-
Intrinsic signalling factors associated with cancer cell-cell fusion
Cell Communication and Signaling (2023)
-
Pax7+ Satellite Cells in Human Skeletal Muscle After Exercise: A Systematic Review and Meta-analysis
Sports Medicine (2023)
-
Adult stem cell sources for skeletal and smooth muscle tissue engineering
Stem Cell Research & Therapy (2022)
-
Spelling Out CICs: A Multi-Organ Examination of the Contributions of Cancer Initiating Cells’ Role in Tumor Progression
Stem Cell Reviews and Reports (2022)
-
Desmin deficiency affects the microenvironment of the cardiac side population and Sca1+ stem cell population of the adult heart and impairs their cardiomyogenic commitment
Cell and Tissue Research (2022)