Uncovering the Role of Dermal Fibroblasts during Injury-Induced Skin Inflammation
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Skin injury initiates wound healing, a complex process which must be tightly regulated for successful repair. An inflammatory response characterized by the influx of immune cells to the wound is a necessary early stage of the repair process to clear debris and protect against infection. Importantly, inflammation must subsequently be dampened in order for skin cells to repopulate the wound, close the gap in the skin, and restructure the site of the injury. Inflammation is therefore a critical juncture in wound healing, as defects in its induction or resolution can significantly delay or entirely prevent repair. Fibroblasts, found in tissues across the body, are increasingly recognized as contributors to inflammatory processes. This dissertation explores how dermal fibroblasts, a heterogeneous population of spatially-distinct mesenchymal cells, regulate the inflammatory phase of wound healing via communication with the immune cells entering the wound at that time. In Chapter 2, we used single-nuclei RNA sequencing, in vitro analysis, and a knockout mouse model to demonstrate that fibroblasts, particularly those residing in the deeper layers of the skin, upregulate inflammatory cytokines during the inflammatory phase of healing. We validated that fibroblast-derived CCL2 is critical for recruiting macrophages to the wound, and loss of it leads to delays in wound closure and revascularization. In Chapter 3, we expanded on this analysis by exploring fibroblast-immune communication throughout the early, peak, and late stages of injury-induced inflammation using single-cell RNA sequencing and predictive communication tools. We found that fibroblasts alter their gene expression as the inflammatory stage progresses, initially adopting a pro-inflammatory, immune-recruiting gene expression profile and subsequently downregulating inflammatory genes in favor of a pro-healing, pro-fibrotic phenotype. Notably, predicted communication networks to immune cells were different for spatially-distinct fibroblast subsets
rather, they are active, dynamic contributors to the immune cell dynamics during this time in ways that are spatially and temporally distinct. This research lays the groundwork for further exploration into how mesenchymal cells regulate immune cell activity in the skin, which is applicable to pathologies associated with defective wound repair or other skin conditions.
pro-inflammatory networks generally originated from deep fibroblasts, while both deep and superficial fibroblasts contributed to anti-inflammatory, pro-healing communication axes, especially during late inflammation. Overall, this project highlights that dermal fibroblasts are not bystanders during skin inflammation
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