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

J Cell Biol. 2014 Apr 14;205(1):97-111. doi: 10.1083/jcb.201310035. Epub 2014 Apr 7.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Cell Fusion
  • Cell Line
  • Cell Movement*
  • Cell Polarity
  • 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
  • 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*
  • Myoblasts, Skeletal / metabolism*
  • Myoblasts, Skeletal / pathology
  • Myoblasts, Skeletal / transplantation*
  • Neuropeptides / metabolism
  • PAX7 Transcription Factor / genetics
  • Phosphoproteins / metabolism
  • Promoter Regions, Genetic
  • Receptors, G-Protein-Coupled / deficiency
  • Receptors, G-Protein-Coupled / genetics
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction
  • Wnt Proteins / genetics
  • Wnt Proteins / metabolism*
  • rac1 GTP-Binding Protein / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • DVL2 protein, human
  • Dishevelled Proteins
  • Dvl2 protein, mouse
  • FZD7 protein, human
  • Frizzled Receptors
  • Fzd7 protein, mouse
  • Luminescent Proteins
  • Neuropeptides
  • PAX7 Transcription Factor
  • Pax7 protein, mouse
  • Phosphoproteins
  • RAC1 protein, human
  • Rac1 protein, mouse
  • Receptors, G-Protein-Coupled
  • Recombinant Fusion Proteins
  • WNT7A protein, human
  • Wnt Proteins
  • Wnt7a protein, mouse
  • red fluorescent protein
  • Green Fluorescent Proteins
  • rac1 GTP-Binding Protein