Wound repair is a tightly regulated process which, when disturbed, can result in incomplete or hypertrophic scarring. β-catenin regulates expression of genes involved in would repair through formation of a transcription activation complex with T cell factor (Tcf). While β-catenin-producing cells are present within skin wounds, it is unclear how β-catenin promotes wound repair and in which cells it is expressed. Using a Tcf reporter mouse model, Saeid Amini-Nik and colleagues at the Peter Gilgan Center for Research identified macrophages as the β-catenin-producing cells within wounds. Tcf-active cells were primarily of the myeloid lineage in wounded dermal tissue, and myeloid cell-specific ablation of β-catenin resulted in the inability to close skin wounds. Genes involved in migration and adhesion were downregulated in β-catenin-deficient macrophages, and as a result, these macrophages were defective in fibroblast adhesion and migration. Macrophages lacking β-catenin also made less TGF-β, which is necessary for fibroblast proliferation, and administration of recombinant TGF-β restored wound repair in β-catenin-deficient mice. The findings in mice were paralleled by examination of human hypertrophic scar tissue, which revealed increased numbers of macrophage and β-catenin-expressing cells compared to normal scar samples. Macrophage number also correlated with scar size. This work indicates that β-catenin mediates scar size through regulation of macrophage migration, adhesion, and differentiation and a better understanding of wound repair regulation will inform future treatments for chronic or refractory wounds. The accompanying image of a wound from a myeloid lineage reporter mouse shows myeloid cells (green) in the dermal tissue of healing skin (right half of image), where cells beneath the upper keratin layer (red) are proliferating (DAPI-blue).
A β-catenin/T cell factor–dependent transcriptional program is critical during cutaneous wound repair for the regulation of scar size; however, the relative contribution of β-catenin activity and function in specific cell types in the granulation tissue during the healing process is unknown. Here, cell lineage tracing revealed that cells in which β-catenin is transcriptionally active express a gene profile that is characteristic of the myeloid lineage. Mice harboring a macrophage-specific deletion of the gene encoding β-catenin exhibited insufficient skin wound healing due to macrophage-specific defects in migration, adhesion to fibroblasts, and ability to produce TGF-β1. In irradiated mice, only macrophages expressing β-catenin were able to rescue wound-healing deficiency. Evaluation of scar tissue collected from patients with hypertrophic and normal scars revealed a correlation between the number of macrophages within the wound, β-catenin levels, and cellularity. Our data indicate that β-catenin regulates myeloid cell motility and adhesion and that β-catenin–mediated macrophage motility contributes to the number of mesenchymal cells and ultimate scar size following cutaneous injury.
Saeid Amini-Nik, Elizabeth Cambridge, Winston Yu, Anne Guo, Heather Whetstone, Puviindran Nadesan, Raymond Poon, Boris Hinz, Benjamin A. Alman