β-Catenin–regulated myeloid cell adhesion and migration determine wound healing
Saeid Amini-Nik, … , Boris Hinz, Benjamin A. Alman
Saeid Amini-Nik, … , Boris Hinz, Benjamin A. Alman
Published June 2, 2014; First published May 16, 2014
Citation Information: J Clin Invest. 2014;124(6):2599-2610. https://doi.org/10.1172/JCI62059.
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Categories: Research Article Immunology

β-Catenin–regulated myeloid cell adhesion and migration determine wound healing

Abstract

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.

Authors

Saeid Amini-Nik, Elizabeth Cambridge, Winston Yu, Anne Guo, Heather Whetstone, Puviindran Nadesan, Raymond Poon, Boris Hinz, Benjamin A. Alman

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Figure 1

Tcf transcriptionally active cells express genes characteristic of macrophages during skin healing.

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(A) Dermal component of a healing wound in a Tcf reporter mouse showing a subpopulation of fibroblast-like cells that were transcriptionally active for β-catenin/Tcf labeled with β-gal. Scale bar: 26 μm. (B) Quantitative RT-PCR analysis showing a higher expression level of genes known to be expressed in macrophages in β-gal–positive cells compared with expression levels of these genes in β-gal–negative cells. Data are shown as the mean ± 95% CI of results from 8 mice. (C) Double immunofluorescence staining of intact skin from a Lysz-Cre ROSA-EYFP mouse showing that EYFP-positive cells were also positive for F4/80. Arrows indicate EYFP-positive myeloid cells. In unwounded mice, EYFP-positive cells were also positive for F4/80. (D) Double immunofluorescence staining of intact skin from a Lysz-Cre ROSA-EYFP mouse showing that macrophages (EYFP-positive cells) in the unwounded skin did not express β-catenin. Arrows show EYFP-positive cells, and arrowheads show EYFP- and β-catenin–positive cells. (E) Double immunofluorescence staining of granulation tissue of healing wounds from a Lysz-Cre ROSA-EYFP mouse showing colocalization of EYFP and β-catenin in EYFP-positive cells. Arrows show EYFP-positive/β-catenin–positive cells, and arrowheads show EYFP-negative/β-catenin–positive cells, indicating that β-catenin was expressed in myeloid cells during the healing process. (F) Double immunofluorescence staining of the wound granulation tissue from a Lysz-Cre ROSA-EYFP Tcf mouse showing colocalization of EYFP and β-gal. Arrows show EYFP-positive/β-gal–positive cells, and arrowheads show EYFP-negative/β-gal–positive cells, indicating that myeloid cells exhibited β-catenin–dependent Tcf-mediated transcriptional activity during healing. (C–F) Pie charts illustrating the proportion of positive and negative stained cells in samples from 8 mice. Scale bars: 50 μm.