Fibroblast migration is mediated by CD44-dependent TGFβ activation
Abstract
CD44 contributes to inflammation and fibrosis in response to injury. As fibroblast recruitment is critical to wound healing, we compared cytoskeletal architecture and migration of wild-type (CD44WT) and CD44-deficient (CD44KO) fibroblasts. CD44KO fibroblasts exhibited fewer stress fibers and focal adhesion complexes, and their migration was characterized by increased velocity but loss of directionality, compared with CD44WT fibroblasts. Mechanistically, we demonstrate that CD44WT cells generated more active TGFβ than CD44KO cells and that CD44 promotes the activation of TGFβ via an MMP-dependent mechanism. Reconstitution of CD44 expression completely rescued the phenotype of CD44KO cells whereas exposure of CD44KO cells to exogenous active TGFβ rescued the defect in stress fibers and migrational velocity, but was not sufficient to restore directionality of migration. These results resolve the TGFβ-mediated and TGFβ-independent effects of CD44 on fibroblast migration and suggest that CD44 may be critical for the recruitment of fibroblasts to sites of injury and the function of fibroblasts in tissue remodeling and fibrosis.
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TGF-β/Smad signaling, in cooperation with Erk MAPK and Akt-mTOR signaling, promotes activation and myofibroblast differentiation of CAFs, similar to fibroblast differentiation upon wounding and inflammation.
“TGF-β/Smad signaling, in cooperation with Erk MAPK and Akt-mTOR signaling, promotes activation and myofibroblast differentiation of CAFs, similar to fibroblast differentiation upon wounding and inflammation228,251,252.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [251]
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- Authors
- Acharya, P. S., Majumdar, S., Jacob, M., Hayden, J., Mrass, P., Weninger, W., Assoian, R. K., & Puré, E.
- Affiliations
- The Wistar Institute (US)
- University of Pennsylvania (US)
- The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA
- Venue
- Journal of Cell Science
- Publisher
- The Company of Biologists
- Published
- 2008-05-01
- Volume
- 121
- Issue
- 9
- Pages
- 1393-1402
- ISSN
- 0021-9533 (ISSN-L)
- 1477-9137
- OpenAlex
- W2141416258
- Cited by
- 157
- References
- 60
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 2 · 2023: 4 · 2022: 11 · 2021: 13 · 2020: 11 · 2019: 15 · 2018: 7 · 2017: 11 · 2016: 5 · 2015: 15 · 2014: 9 · 2013: 5 · 2012: 7
- FWCI
- 4.23
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Cell Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (T32-HL-07586, R01 HL 65507, R01HL065507, P01HL062250, T32HL007586)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
- Keywords
- CD44, fibroblast migration, TGF-beta activation, stress fibers, focal adhesions, fibroblast recruitment, wound healing, fibrosis, tissue remodeling, cytoskeleton
- MeSH terms
- Animals, Antibodies, Cell Movement, Cytoskeleton, Fibroblasts, Mice, Inbred C57BL, Phenotype, Transforming Growth Factor beta, Hyaluronan Receptors, Matrix Metalloproteinases, Focal Adhesions, Stress Fibers, Mice
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