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

Bentzinger CF, von Maltzahn J, Dumont NA, Stark DA, Wang YX, Nhan K, Frenette J, Cornelison DD, Rudnicki MA - J. Cell Biol. (2014)

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.

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.

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Molecular mechanisms of ex vivo Wnt7a modulation. Upon stimulation, Wnt7a induces the symmetric proliferation of Myf5-independent satellite cells in conjunction with fibronectin (FN1), syndecan-4 (SDC4) and Vangl2 through the planar cell polarity pathway. In myogenic progenitors, Wnt7a also facilitates Rac1-mediated cell polarization and migration. Fusion of Wnt7a-treated cells activates the AKT–mTOR pathway, leading to myofiber hypertrophy. Therefore, Wnt7a acts on three levels to facilitate the outcomes of cell therapy: (1) it boosts stem cell number, (2) facilitates their dispersion in the host tissue, and (3) leads to muscle growth.
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fig8: Molecular mechanisms of ex vivo Wnt7a modulation. Upon stimulation, Wnt7a induces the symmetric proliferation of Myf5-independent satellite cells in conjunction with fibronectin (FN1), syndecan-4 (SDC4) and Vangl2 through the planar cell polarity pathway. In myogenic progenitors, Wnt7a also facilitates Rac1-mediated cell polarization and migration. Fusion of Wnt7a-treated cells activates the AKT–mTOR pathway, leading to myofiber hypertrophy. Therefore, Wnt7a acts on three levels to facilitate the outcomes of cell therapy: (1) it boosts stem cell number, (2) facilitates their dispersion in the host tissue, and (3) leads to muscle growth.

Mentions: Taken together, ex vivo Wnt7a treatment enhances the migration and tissue dispersion of both mouse and human myogenic cells through Dvl2 and the small GTPases. This effect is most pronounced in, but not limited to, satellite cells, indicating that committed myogenic progenitors readily activate noncanonical signaling in response to Wnt7a. We conclude that Wnt7a has several therapeutically attractive properties that modulate muscle regeneration at multiple levels, including the stimulation of motility and engraftment (Fig. 8).


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

Bentzinger CF, von Maltzahn J, Dumont NA, Stark DA, Wang YX, Nhan K, Frenette J, Cornelison DD, Rudnicki MA - J. Cell Biol. (2014)

Molecular mechanisms of ex vivo Wnt7a modulation. Upon stimulation, Wnt7a induces the symmetric proliferation of Myf5-independent satellite cells in conjunction with fibronectin (FN1), syndecan-4 (SDC4) and Vangl2 through the planar cell polarity pathway. In myogenic progenitors, Wnt7a also facilitates Rac1-mediated cell polarization and migration. Fusion of Wnt7a-treated cells activates the AKT–mTOR pathway, leading to myofiber hypertrophy. Therefore, Wnt7a acts on three levels to facilitate the outcomes of cell therapy: (1) it boosts stem cell number, (2) facilitates their dispersion in the host tissue, and (3) leads to muscle growth.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3987134&req=5

fig8: Molecular mechanisms of ex vivo Wnt7a modulation. Upon stimulation, Wnt7a induces the symmetric proliferation of Myf5-independent satellite cells in conjunction with fibronectin (FN1), syndecan-4 (SDC4) and Vangl2 through the planar cell polarity pathway. In myogenic progenitors, Wnt7a also facilitates Rac1-mediated cell polarization and migration. Fusion of Wnt7a-treated cells activates the AKT–mTOR pathway, leading to myofiber hypertrophy. Therefore, Wnt7a acts on three levels to facilitate the outcomes of cell therapy: (1) it boosts stem cell number, (2) facilitates their dispersion in the host tissue, and (3) leads to muscle growth.
Mentions: Taken together, ex vivo Wnt7a treatment enhances the migration and tissue dispersion of both mouse and human myogenic cells through Dvl2 and the small GTPases. This effect is most pronounced in, but not limited to, satellite cells, indicating that committed myogenic progenitors readily activate noncanonical signaling in response to Wnt7a. We conclude that Wnt7a has several therapeutically attractive properties that modulate muscle regeneration at multiple levels, including the stimulation of motility and engraftment (Fig. 8).

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.

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.

Show MeSH
Related in: MedlinePlus