Wnt3a Induces Myofibroblast Differentiation by Upregulating TGF-β Signaling Through SMAD2 in a β-Catenin-Dependent Manner
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Growing evidence suggests the Wnt family of secreted glycoproteins and their associated signaling pathways, linked to development, are recapitulated during wound repair and regeneration events. However, the role of the Wnt pathway in such settings remains unclear. In the current study, we treated mouse fibroblasts with 250 ng/mL of recombinant Wnt3a for 72 hours and examined its affect on cell morphology and function. Wnt3a induced a spindle-like morphology in fibroblasts characterized by the increased formation of stress fibres. Wnt3a decreased the proliferation of fibroblasts, but significantly increased cell migration as well as fibroblast-mediated contraction of a collagen lattice. Wnt3a significantly increased the expression of TGF-β and its associated signaling through SMAD2. Consistent with this, we observed significantly increased smooth muscle α-actin expression and incorporation of this contractile protein into stress fibres following Wnt3a treatment. Knockdown of β-catenin using siRNA reversed the Wnt3a-induced smooth muscle α-actin expression, suggesting these changes were dependent on canonical Wnt signaling through β-catenin. Neutralization of TGF-β with a blocking antibody significantly inhibited the Wnt3a-induced smooth muscle α-actin expression, indicating these changes were dependent on the increased TGF-β signaling. Collectively, this data strongly suggests Wnt3a promotes the formation of a myofibroblast-like phenotype in cultured fibroblasts, in part, by upregulating TGF-β signaling through SMAD2 in a β-catenin-dependent mechanism. As myofibroblasts are critical regulators of wound healing responses, these findings may have important implications for our understanding of normal and aberrant injury and repair events.
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Synergistic crosstalk between TGFβ and Wnt in myofibroblast activation is documented, and SFRP2 has an inhibitory role in TGFβ-dependent myofibroblast formation and post-inflammatory fibrosis.
“The synergistic crosstalk between TGFβ and Wnt signaling in the myofibroblast activation is documented as well as the inhibitory role of SFRP2 in the TGFβ-dependent myofibroblast formation and post-inflammatory fibrosis [138,139].”
From Cellular and Molecular Mechanisms in the Pathogenesis of Classical, Vascular, and Hypermobile Ehlers‒Danlos Syndromes (2019) · cites this paper as [138]
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- Authors
- Carthy, J. M., Garmaroudi, F. S., Luo, Z., & McManus, B. M.
- Affiliations
- University of British Columbia (CA)
- Corresponding author
- McManus, Bruce M.
- ORCID
- McManus, Bruce M.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2011-05-18
- Volume
- 6
- Issue
- 5
- Pages
- e19809
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3097192
- OpenAlex
- W2039378503
- Cited by
- 172
- References
- 32
- Citations by year
- 2026: 9 · 2025: 6 · 2024: 7 · 2023: 9 · 2022: 9 · 2021: 9 · 2020: 17 · 2019: 9 · 2018: 11 · 2017: 15 · 2016: 8 · 2015: 18 · 2014: 17 · 2013: 9 · 2012: 14
- FWCI
- 5.84
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Heart and Stroke Foundation of Canada
- Heart and Stroke Foundation of British Columbia and Yukon
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
- Keywords
- Wnt3a, myofibroblast differentiation, TGF-beta signaling, Smad2, β-catenin, Wnt/β-catenin signaling, fibroblasts, smooth muscle actin, stress fibers, cell migration, collagen lattice contraction, wound healing, tissue regeneration
- MeSH terms
- Actins, Animals, Cell Differentiation, Cell Movement, Collagen, Gels, Muscle, Smooth, Phenotype, Phosphorylation, Signal Transduction, Up-Regulation, Transforming Growth Factor beta, Stress Fibers, Cell Shape, Cell Proliferation, Wnt Proteins, beta Catenin, Mice, Smad2 Protein, Myofibroblasts, Wnt3 Protein, Wnt3A Protein
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