Myofibroblast proliferation and heterogeneity are supported by macrophages during skin repair

Abstract

During tissue repair, myofibroblasts produce extracellular matrix (ECM) molecules for tissue resilience and strength. Altered ECM deposition can lead to tissue dysfunction and disease. Identification of distinct myofibroblast subsets is necessary to develop treatments for these disorders. Here, using extensive analysis of pro-fibrotic cells during mouse skin wound healing, fibrosis and aging; we identify distinct subpopulations of myofibroblasts, including cells identified as adipocyte precursors (APs). Multiple mouse models and transplantation assays demonstrate that AP proliferation, and not other myofibroblasts, is activated by CD301b-expressing macrophages through IGF1 and PDGFC. With age, wound bed APs and differential gene expression between myofibroblast subsets are reduced. Our findings identify multiple fibrotic cell populations and suggest the environment dictates functional myofibroblast heterogeneity, which is driven by fibroblast-immune interactions after wounding.

Cold atmospheric pressure plasmas in dermatology: Sources, reactive agents, and therapeutic effects

“…Facing the global problems of aging of populations and antibiotic overuse, it has become more difficult to treat skin diseases, and new treatment approaches are needed. [ 16–18 ] CAP can not only sterilize common pathogenic and antibiotic‐resistant Staphylococcus aureus and Escherichia coli bacteria without harming normal cells of the skin sample, [ 19 ] but also stimulate the proliferation of mammalian cells. [ 20 ] The multiple modes of action of CAP in skin treatment include killing the microbes, tissue stimulation, anti‐inflammatory, and anti‐itch property, which make CAP ideal for dermatological applications in the treatment of inflammatory diseases and wound healing.…”

A multiscale hybrid mathematical model of epidermal‐dermal interactions during skin wound healing

“…Shook et al. showed that unwounded mouse skin contains three fibroblast populations, that one of them shares high similarity with En1 ‐positive cells, and that their contributions to wound healing are distinct. Using single‐cell RNA‐sequencing, our group showed that early wound scars in mice contain as many as twelve fibroblast clusters and that they form at least three distinct fibroblast differentiation trajectories.…”

“…Both compartments were modelled independently and separated by a dynamic interface, termed Ω . During wound healing, ECM production and fibroblast proliferation are known to be regulated by multiple signalling factors. Key signalling factors involved in wound healing are members of the TGF pathway, although their effects are complex.…”

“…This suggests that TGFβ1 serves an activator for fibroblast proliferation and ECM production, whereas TGFβ3 works as an inhibitor of ECM production. Signalling factors belonging to canonical WNT and PDGF pathways also regulate fibroblast activity and can serve the role of activators and inhibitors in the model.…”

“…In terms of its limitations, our model does not consider potential heterogeneity in skin fibroblast populations, and the possibility that different fibroblast subtypes can respond differently to signalling cues and exert distinct effects on wound healing. Indeed, several recent studies have identified distinct populations of mouse skin fibroblasts with distinct roles in ECM deposition during development and wound healing. Rinkevich et al identified two populations of mouse skin fibroblasts: En1 (Engrailed homeobox 1)‐negative and En1 ‐positive cells.…”