Harnessing the Secretome of Hair Follicle Fibroblasts to Accelerate Ex Vivo Healing of Human Skin Wounds

Abstract

In skin homeostasis, dermal fibroblasts are responsible for coordinating the migration and differentiation of overlying epithelial keratinocytes. As hairy skin heals faster than nonhairy skin, we took bio-inspiration from the follicle and hypothesized that follicular fibroblasts would accelerate skin re-epithelialization after injury faster than interfollicular fibroblasts. Using both in vitro and ex vivo models of human skin wound closure, we found that hair follicle dermal papilla fibroblasts could accelerate closure of in vitro scratch wounds by 1.8-fold and epithelial growth capacity by 1.5-fold compared with controls (P < 0.05). We used a cytokine array to determine how the dermal papilla fibroblasts were eliciting this effect and identified two cytokines, sAXL and CCL19, that are released at significantly higher levels by follicular fibroblasts than by interfollicular subtypes. Using sAXL and CCL19 individually, we found that they could also increase closure of epithelial cells in a scratch wound by 1.2-and 1.5-fold, respectively, compared with controls (P < 0.05). We performed an unbiased transcriptional analysis, combined with pathway analysis, and postulate that sAXL accelerates wound closure by promoting migration and inhibiting epithelial differentiation of skin keratinocytes. Long term, we believe these results can be exploited to accelerate wound closure of human skin in vivo.

Wound healing in aged skin exhibits systems-level alterations in cellular composition and cell-cell communication

“…HF fibroblast-derived CCL19 has been shown to accelerate wound closure in human experimental models ( Topouzi et al, 2020 ). In this context, our finding of reduced Ccl19 expression in aged skin and wounds suggests that Ccl19 may play a similar role in mouse wound healing, and its reduction may contribute to delayed healing in aged skin.…”

Anagen hair follicles transplanted into mature human scars remodel fibrotic tissue

“…5b ). Due to previous reports on the role of hair follicle secretome in both physiological and pathological skin remodelling 33 , 34 , we hypothesized that hair follicles might contribute to scar remodelling via paracrine signaling. To identify changes to the cytokine milieu of mature scars after hair follicle transplantation, we performed another analysis of the core transcriptional signature (231 transcripts) using the IPA software and selected all secreted upstream regulators ( P < 0.05) (Supplementary Table 2 ).…”

Light‐controlled scaffold‐ and serum‐free hard palatal‐derived mesenchymal stem cell aggregates for bone regeneration

“…This can be an advantage as cell migration is essential for various biological functions. 53 Considering the potential application in osseointegration acceleration and bone defect healing, PMSCs were evaluated for its osteogenic capacity and tolerance to inflammation. In consistence with the results of trilineage differentiation assay, PMSCs showed positive response to osteogenic induction despite the degree of increase in osteogenic genes was relatively lower than BMSCs.…”

“…Cell scratch assays indicated excellent cell migration ability of these oral mucosa‐derived cells. This can be an advantage as cell migration is essential for various biological functions 53 . Considering the potential application in osseointegration acceleration and bone defect healing, PMSCs were evaluated for its osteogenic capacity and tolerance to inflammation.…”