Wnt7a stimulates myogenic stem cell motility and engraftment resulting in improved muscle strength.
Wnt7a/Fzd7 signaling stimulates skeletal muscle growth and repair by inducing the symmetric expansion of satellite stem cells through the planar cell polarity pathway and by activating the Akt/mTOR growth pathway in muscle fibers. Here we describe a third level of activity where Wnt7a/Fzd7 increases the polarity and directional migration of mouse satellite cells and human myogenic progenitors through activation of Dvl2 and the small GTPase Rac1. Importantly, these effects can be exploited to potentiate the outcome of myogenic cell transplantation into dystrophic muscles. We observed that a short Wnt7a treatment markedly stimulated tissue dispersal and engraftment, leading to significantly improved muscle function. Moreover, myofibers at distal sites that fused with Wnt7a-treated cells were hypertrophic, suggesting that the transplanted cells deliver activated Wnt7a/Fzd7 signaling complexes to recipient myofibers. Taken together, we describe a viable and effective ex vivo cell modulation process that profoundly enhances the efficacy of stem cell therapy for skeletal muscle.
Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
C Florian
CF
Bentzinger
Julia
J
von Maltzahn
Nicolas A
NA
Dumont
Danny A
DA
Stark
Yu Xin
YX
Wang
Kevin
K
Nhan
Jérôme
J
Frenette
D D W
DD
Cornelison
Michael A
MA
Rudnicki
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D002459:Cell Fusion; D002460:Cell Line; D002465:Cell Movement; D016764:Cell Polarity; D004195:Disease Models, Animal; D000072261:Dishevelled Proteins; D004705:Endocytosis; D051157:Frizzled Receptors / Q000378:metabolism; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006984:Hypertrophy; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018101:Mice, Inbred mdx; D018345:Mice, Knockout; D008822:Mice, Transgenic; D053580:Muscle Strength; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D009136:Muscular Dystrophies / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D032448:Myoblasts, Skeletal / Q000378:metabolism* / Q000473:pathology / Q000637:transplantation*; D009479:Neuropeptides / Q000378:metabolism; D051763:PAX7 Transcription Factor / Q000235:genetics; D010750:Phosphoproteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D000097573:Red Fluorescent Protein
D048868:Adaptor Proteins, Signal Transducing; D000072261:Dishevelled Proteins; D051157:Frizzled Receptors; D049452:Green Fluorescent Proteins; D008164:Luminescent Proteins; D009479:Neuropeptides; D051763:PAX7 Transcription Factor; D010750:Phosphoproteins; D043562:Receptors, G-Protein-Coupled; D011993:Recombinant Fusion Proteins; D051153:Wnt Proteins; D020830:rac1 GTP-Binding Protein; D000097573:Red Fluorescent Protein; C000606581:DVL2 protein, human; C000606582:Dvl2 protein, mouse; C115810:FZD7 protein, human; C492041:Fzd7 protein, mouse; C497322:Pax7 protein, mouse; C107953:RAC1 protein, human; C484602:Rac1 protein, mouse; C092778:WNT7A protein, human; C490508:Wnt7a protein, mouse