Cells from adult bone marrow participate in the regeneration of damaged skeletal myofibers. However, the relationship of these cells with the various hematopoietic and nonhematopoietic cell types found in bone marrow is still unclear. Here we show that the progeny of a single cell can both reconstitute the hematopoietic system and contribute to muscle regeneration. Integration of bone marrow cells into myofibers occurs spontaneously at low frequency and increases with muscle damage. Thus, classically defined single hematopoietic stem cells can give rise to both blood and muscle.
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Gussoni, E. et al. Dystrophin expression in the mdx mouse restored by stem cell transplantation. Nature 401, 390–394 (1999).
Ferrari, G. et al. Muscle regeneration by bone marrow-derived myogenic progenitors. Science 279, 1528–1530 (1998).
Gussoni, E. et al. Long-term persistence of donor nuclei in a Duchenne muscular dystrophy patient receiving bone marrow transplantation. J. Clin. Invest. 110, 807–814 (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).
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).
Krause, D.S. et al. Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell 105, 369–377 (2001).
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).
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).
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).
Ramalho-Santos, M., Yoon, S., Matsuzaki, Y., Mulligan, R.C. & Melton, D.A. “Stemness”: transcriptional profiling of embryonic and adult stem cells. Science 298, 597–600 (2002).
Zhou, S. et al. Bcrp1 gene expression is required for normal numbers of side population stem cells in mice, and confers relative protection to mitoxantrone in hematopoietic cells in vivo. Proc. Natl. Acad. Sci. USA 99, 12339–12344 (2002).
Brazelton, T.R., Nystrom, M. & Blau, H.M. Significant differences among skeletal muscles in the incorporation of bone marrow-derived cells. Dev. Biol. 262, 64–74 (2003).
Dixon, R.W. & Harris, J.B. Myotoxic activity of the toxic phospholipase, notexin, from the venom of the Australian tiger snake. J. Neuropathol. Exp. Neurol. 55, 1230–1237 (1996).
Weissman, I.L. Stem cells: units of development, units of regeneration, and units in evolution. Cell 100, 157–168 (2000).
Siminovitch, I., McCulloch, E. & Till, J. The distribution of colony-forming cells among spleen colonies. J. Cell. Physiol. 62, 327–336 (1963).
Blau, H.M., Brazelton, T.R. & Weimann, J.M. The evolving concept of a stem cell: entity or function? Cell 105, 829–841 (2001).
Terada, N. et al. Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature 416, 542–545 (2002).
Ying, Q.L., Nichols, J., Evans, E.P. & Smith, A.G. Changing potency by spontaneous fusion. Nature 416, 545–548 (2002).
Blau, H.M. et al. Plasticity of the differentiated state. Science 230, 758–766 (1985).
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).
Wang, X. et al. Cell fusion is the principal source of bone-marrow-derived hepatocytes. Nature 422, 897–901 (2003).
Vassilopoulos, G., Wang, P.R. & Russell, D.W. Transplanted bone marrow regenerates liver by cell fusion. Nature 422, 901–904 (2003).
Weimann, J.M., Johansson, C.B., Trejo, A. & Blau, H.M. Stable reprogrammed heterokaryons form spontaneously in Purkinje neurons in adult brain. Nat. Cell Biol. (in the press).
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).
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).
We thank A. Johnson for help with flow cytometry, and R. Doyonnas, K. McNagny and M. Labarge for useful comments. T.R.B. was supported by a Lutheran Brotherhood Fellowship and by National Institutes of Health predoctoral training grant GM07149. H.M.B. was supported by NIH grants HD18179, HL65572, AG09521 and AG2096l, and by Ellison Foundation grant AG-SS-0817. F.M.V.R. is supported by a Canada Research Chair in Regenerative Medicine. This work was supported by Canadian Institutes of Health Research grant MOP-53332 and from the Networks of Centres of Excellence–Stem Cell Network Plasticity Project funding to F.M.V.R.
The authors declare no competing financial interests.
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