During wound repair, fibroblasts move across tissue defects, and cause contraction of the extracellular matrix. Fibroblast motility is initiated when a cell extends a protrusion at its front which attaches to the substratum on which the cell is migrating, followed by a contraction that moves the cell body forward toward the protrusion, and finally the attachments at the cell rear release as the cell moves forward. The ability of fibroblasts to induce contraction of a collagen lattice is related to activation of fibroblast contractile machinery, the ability to transmit the contractile force to the extracellular matrix, and to the remodeling of the matrix. We found that different signaling pathways regulate these processes, suggesting that these two processes are controlled by different intracellular mechanisms.
Fibroblast activation to myofibroblasts is mediated by α-smooth muscle actin, and can be induced by transforming growth factor β. This is one mechanism by which transforming growth factor β can activate the fibroblast contractile machinery [11, 32]. We found that in contrast to transforming growth factor β, β-catenin does not regulate α-smooth muscle actin expression. This finding that is consistent with data from human wound healing. Although α-smooth muscle actin is elevated during the wound healing process, its expression does not vary significantly during the first few weeks of wound repair, a time during which β-catenin level shows substantial variation. Taken together, this suggests that β-catenin mediated tcf-dependent transcription does not directly regulate α-smooth muscle actin expression in fibrobasts.
We found little effect of transforming growth factor β on fibroblast motility. This is in agreement with studies suggesting an inhibitory effect of transforming growth factor β on fibroblast motility [13, 33]. However, transforming growth factor β has also been shown to activate cell motility on certain cell surfaces . This suggests that it has different effects depending on the environment in which the fibroblast resides. In contrast to transforming growth factor β, β-catenin was found to positively regulate cell motility. Our findings are in agreement with developmental data, in which canonical Wnt signaling can regulate cell migration, such as in cardiac progenitors, whose migration is controlled by β-catenin signaling . Cell motility is an integral process in wound repair, as cells need to migrate to cross the tissue defect. This is a complex process, during which a cell extends a protrusion at its front, which in turn attaches to the substratum on which the cell is migrating. This is followed by a contraction that moves the cell body forward toward the protrusion, and finally the attachments at the cell rear release as the cell continues to move forward. Chemotactic agents initiate this cycle, and intracellular processes, such as actomyosin filament contraction, which proposes the cell forward, and the formation of adhesive connections in the front, and release of adhesion in the rear of the cell are responsible for propelling the cell. β-catenin participates in adherens junctions, actin cytoskeleton binding, and transcriptional regulation. Participation in each of these processes could regulate cell migration.
During wound repair, numerous factors contribute to wound size including the number of cells present (a function of cell proliferation and migration) and the behavior of the cells within the extracellular matrix. Activation of number of signaling pathways, such as through transforming growth factor β and β-catenin, cause a larger wound size. Our data, in concert with data from previous studies, suggests that these two signaling pathways activate different cellular processes to produce a larger wound size. Both transforming growth factor β and β-catenin positively regulate fibroblast proliferation, suggesting that this is a common cellular process in the generation of a hypertrophic wound. In contrast β-catenin has a dominant role regulates cell motility while transforming growth factor β has a dominant role regulating lattice contraction. Such data likely has important implications in therapeutic approaches to hyperplasic wound healing, as the modulation of a multiple involved signaling pathways may be required.