Wnt signaling induces the myogenic specification of resident CD45+ adult stem cells during muscle regeneration.
The observation that CD45(+) stem cells injected into the circulation participate in muscle regeneration raised the question of whether CD45(+) stem cells resident in muscle play a physiological role during regeneration. We found that CD45(+) cells cultured from uninjured muscle were uniformly nonmyogenic. However, CD45(+) cells purified from regenerating muscle readily gave rise to determined myoblasts. The number of CD45(+) cells in muscle rapidly expanded following injury, and a high proportion entered the cell cycle. Investigation of candidate pathways involved in embryonic myogenesis revealed that Wnt signaling was sufficient to induce the myogenic specification of muscle-derived CD45(+) stem cells. Moreover, injection of the Wnt antagonists sFRP2/3 into regenerating muscle markedly reduced CD45(+) stem cell proliferation and myogenic specification. Our data therefore suggest that mobilization of resident CD45(+) stem cells is an important factor in regeneration after injury and highlight the Wnt pathway as a potential therapeutic target for degenerative neuromuscular disease.
Polesskaya
Anna
A
Ottawa Health Research Institute, Molecular Medicine Program, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6.
Seale
Patrick
P
Rudnicki
Michael A
MA
D000818:Animals; D015415:Biomarkers; D002454:Cell Differentiation / Q000235:genetics*; D002455:Cell Division / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000378:metabolism; D051157:Frizzled Receptors; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D017493:Leukocyte Common Antigens / Q000276:immunology*; D008094:Lithium / Q000494:pharmacology; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D032446:Myoblasts / Q000276:immunology / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D012038:Regeneration / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D013234:Stem Cells / Q000276:immunology / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; D000094742:Secreted Frizzled-Related Proteins
D015415:Biomarkers; D003598:Cytoskeletal Proteins; D051157:Frizzled Receptors; D017493:Leukocyte Common Antigens; D008094:Lithium; D008565:Membrane Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D015534:Trans-Activators; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; C495267:CTNNB1 protein, mouse; C498581:Fzd4 protein, mouse; C491628:Sfrp2 protein, mouse; D000094742:Secreted Frizzled-Related Proteins