Fibroblast-Mediated Macrophage Recruitment Supports Acute Wound Healing
Veronica M. Amuso, MaryEllen R. Haas, Paula O. Cooper, Ranojoy Chatterjee, Sana Hafiz, Shatha Salameh, Chiraag Gohel, Miguel F. Mazumder, Violet Josephson, Sarah S Kleb, Khatereh Khorsandi, Anélia Horvath, Ali Rahnavard, Brett A. Shook
Abstract
Epithelial and immune cells have long been appreciated for their contribution to the early immune response after injury; however, much less is known about the role of mesenchymal cells. Using single-nuclei RNA sequencing, we defined changes in gene expression associated with inflammation 1 day after wounding in mouse skin. Compared with those in keratinocytes and myeloid cells, we detected enriched expression of proinflammatory genes in fibroblasts associated with deeper layers of the skin. In particular, SCA1+ fibroblasts were enriched for numerous chemokines, including CCL2, CCL7, and IL-33, compared with SCA1- fibroblasts. Genetic deletion of Ccl2 in fibroblasts resulted in fewer wound-bed macrophages and monocytes during injury-induced inflammation, with reduced revascularization and re-epithelialization during the proliferation phase of healing. These findings highlight the important contribution of fibroblast-derived factors to injury-induced inflammation and the impact of immune cell dysregulation on subsequent tissue repair.