Adult skin fibroblast state change in murine wound healing

Abstract

Wound healing is a well-organized dynamic process involving coordinated consecutive phases: homeostasis, inflammation, proliferation and resolution. Fibroblasts play major roles in skin wound healing such as in wound contraction and release of growth factors which are of importance in angiogenesis and tissue remodeling. Abnormal fibroblast phenotypes have been identified in patients with chronic wounds. In this work, we analyzed scRNA-seq datasets of normal and wounded skin from mice at day 4 post-wound to investigate fibroblast heterogeneity during the proliferative phase of wound healing. Compositional analysis revealed a specific subset of fibroblast (cluster 3) that primarily increased in wounded skin (14%) compared to normal skin (3.9%). This subset was characterized by a gene signature marked by the plasma membrane proteins Sfrp2 + Sfrp4 + Sfrp1 + and the transcription factors Ebf1 + Prrx1 + Maged1 + . Differential gene expression and enrichment analysis identified epithelial to mesenchymal transition (EMT) and angiogenesis to be upregulated in the emerging subset of fibroblasts of the wounded skin. Using two other datasets for murine wounded skin confirmed the increase in cluster 3-like fibroblasts at days 2, 7 and 14 post-wounding with a peak at day 7. By performing a similarity check between the differential gene expression profile between wounded and normal skin for this emerging fibroblast subset with drug signature from the ConnectivityMap database, we identified drugs capable of mimicking the observed gene expression change in fibroblasts during wound healing. TTNPB, verteprofin and nicotinic acid were identified as candidate drugs capable of inducing fibroblast gene expression profile necessary for wound healing. On the other hand, methocarbamol, ifosfamide and penbutolol were recognized to antagonize the identified fibroblast differential expression profile during wound healing which might cause delay in wound healing. Taken together, analysis of murine transcriptomic skin wound healing datasets suggested a subset of fibroblasts capable of inducing EMT and further inferred drugs that might be tested as potential candidates to induce wound closure.

A genome‐wide association study meta‐analysis in a European sample of stage III/IV grade C periodontitis patients ≤35 years of age identifies new risk loci

“…Moreover, it is a constitutive component of the interleukin‐3 receptor complex, is involved in neutrophil and platelet activation and may function cooperatively with other activating receptors. Interestingly, FCER1G was among the top up‐regulated genes involved in granulocyte chemotaxis in wounded mouse skin (Gharbia et al, 2023). Additionally, studies have demonstrated that ITAM‐containing Fc receptor common gamma subunits are required for the maintenance of bone homeostasis through activating signals for osteoclastogenesis in mice (Koga et al, 2004) and that FcεRI‐mediated activation in transfected rat basophil leukaemia cells is inhibited by SIGLEC5 (Avril et al, 2005).…”

Secreted frizzled related-protein 2 is prognostic for human pancreatic cancer patient survival and is associated with fibrosis

“…Our observation that SFRP2 and TGF have similar effects on fibroblasts suggests that SFRP2 affects the mesenchymal status of the cells. A previous study on wound healing demonstrated that fibroblasts are predominant in the wound during the proliferation stage [ 36 ]. Importantly, this study showed that fibroblasts have the highest gene expression of EMT markers while concomitantly, SFRP2 is one of the most upregulated plasma membrane proteins.…”

Investigation of multifaceted wound healing effect of exopolysaccharide (EPS) produced from probiotic strain Lactiplantibacillus plantarum GD2 as in vitro and in ovo

“…Fibroblast proliferation is critical for filling the tissue space formed after injury with proliferating fibroblasts and synthesizing the ECM, which is destroyed by an increase in the number of fibroblasts in the wound area [73][74][75][76] . TNF-α levels in circulating plasma are generally around 11 pg/mL while in healthy skin tissue TNF-α levels are about 1.5 ng/mL 77,78 .…”