Wnt7a stimulates myogenic stem cell motility and engraftment resulting in improved muscle strength

• Published in: The Journal of cell biology 2014-04, Vol.205 (1), p.97-111
• Main Authors: Bentzinger, C Florian, von Maltzahn, Julia, Dumont, Nicolas A, Stark, Danny A, Wang, Yu Xin, Nhan, Kevin, Frenette, Jérôme, Cornelison, D D W, Rudnicki, Michael A
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Animals; Cell adhesion & migration; Cell Fusion; Cell Line; Cell Movement; Cell Polarity; Cellular biology; Disease Models, Animal; Dishevelled Proteins; Endocytosis; Frizzled Receptors - metabolism; Genes, Reporter; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; Humans; Hypertrophy; Luminescent Proteins - genetics; Luminescent Proteins - metabolism; Mice; Mice, Inbred mdx; Mice, Knockout; Mice, Transgenic; Motility; Muscle Strength; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Muscle, Skeletal - physiopathology; Muscle, Skeletal - surgery; Muscular Dystrophies - genetics; Muscular Dystrophies - metabolism; Muscular Dystrophies - pathology; Muscular Dystrophies - physiopathology; Muscular Dystrophies - surgery; Muscular system; Myoblasts, Skeletal - metabolism; Myoblasts, Skeletal - pathology; Myoblasts, Skeletal - transplantation; Neuropeptides - metabolism; PAX7 Transcription Factor - genetics; Phosphoproteins - metabolism; Promoter Regions, Genetic; rac1 GTP-Binding Protein - metabolism; Receptors, G-Protein-Coupled - deficiency; Receptors, G-Protein-Coupled - genetics; Recombinant Fusion Proteins - metabolism; Red Fluorescent Protein; Signal Transduction; Stem cells; Wnt Proteins - genetics; Wnt Proteins - metabolism
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.201310035

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.