Abstract
β-Catenin is an important regulator of dermal fibroblasts during cutaneous wound repair. However, the factors that modulate β-catenin activity in this process are not completely understood. We investigated the role of the extracellular matrix in regulating β-catenin and found an increase in β-catenin-mediated Tcf-dependent transcriptional activity in fibroblasts exposed to various extracellular matrix components. This occurs through an integrin-mediated GSK3β-dependent pathway. The physiologic role of this mechanism was demonstrated during wound repair in extra domain A-fibronectin-deficient mice, which exhibited decreased β-catenin-mediated signaling during the proliferative phase of healing. Extra domain A-fibronectin-deficient mice have wounds that fail at a lower tensile strength and contain fewer fibroblasts compared with wild type mice. This phenotype was rescued by genetic or pharmacologic activation of β-catenin signaling. Because fibronectin is a transcriptional target of β-catenin, this suggests the existence of a feedback loop between these two molecules that regulates dermal fibroblast cell behavior during wound repair.
Highlights
-Catenin is an important regulator of the wound phenotype during healing, where it modulates dermal fibroblast activity
The lack of a change in wound size or cellularity contrasts starkly with data from mice expressing a conditional null allele of -catenin activated using an identical adenovirus but that expresses Cre-recombinase instead of DKK-1, as previously reported [6]. This suggests that an alternative pathway other than Wnt ligand activation plays a role in maintaining the -catenin protein level during the proliferative phase of cutaneous wound repair
NIH3T3 fibroblasts grown on extracellular matrix components demonstrated increased activated -catenin protein and transcriptional activity, similar to that observed in primary dermal fibroblast cultures, whereas this effect was absent in the 1-integrin null GD25 cells (Fig. 4, B and C)
Summary
T-cell factor; GSK, glycogen-synthase kinase; GFP, green fluorescent protein; FAP, fibroblast activation protein; EDA, extra domain A; DKK-1, Dickkopf-1; ECM, extracellular matrix. Fibronectin and -Catenin ing wound healing in post-natal mice [17,18,19,20]. Such extracellular matrix factors could modulate -catenin activity during the process of cutaneous healing. We investigate the role of extracellular matrix components in the regulation of -catenin in fibroblasts and examine the role of EDA-fibronectin in relation to -catenin during wound repair in vivo
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