Phagocytosis of Wnt inhibitor SFRP4 by late wound macrophages drives chronic Wnt activity for fibrotic skin healing

Abstract

Human and murine skin wounding commonly results in fibrotic scarring, but the murine wounding model wound-induced hair neogenesis (WIHN) can frequently result in a regenerative repair response. Here, we show in single-cell RNA sequencing comparisons of semi-regenerative and fibrotic WIHN wounds, increased expression of phagocytic/lysosomal genes in macrophages associated with predominance of fibrotic myofibroblasts in fibrotic wounds. Investigation revealed that macrophages in the late wound drive fibrosis by phagocytizing dermal Wnt inhibitor SFRP4 to establish persistent Wnt activity. In accordance, phagocytosis abrogation resulted in transient Wnt activity and a more regenerative healing. Phagocytosis of SFRP4 was integrin-mediated and dependent on the interaction of SFRP4 with the EDA splice variant of fibronectin. In the human skin condition hidradenitis suppurativa, phagocytosis of SFRP4 by macrophages correlated with fibrotic wound repair. These results reveal that macrophages can modulate a key signaling pathway via phagocytosis to alter the skin wound healing fate.

Lef1 expression in fibroblasts maintains developmental potential in adult skin to regenerate wounds

“…The activation of beta-catenin in fibroblasts during wound healing has been shown to inhibit hair follicle reformation in scars ( Lim et al, 2018 ; Rognoni et al, 2016 ) while deactivating Wnt signaling inhibited hair reformation ( Myung et al, 2013 ). Moreover, persistent Wnt activity in the dermis has been recently shown to drive WIHN toward fibrotic wound healing ( Gay et al, 2020 ). In contrast, the activation of beta-catenin during development increases hair formation and size ( Chen et al, 2012 ; Enshell-Seijffers et al, 2010 ).…”

Aetiology and pathogenesis of hidradenitis suppurativa

“…1 Macrophage-dependent chronic WNT activity may play a role in fibrotic scarring. 70 HS lesions and adjacent areas also contain areas of interfollicular inflammation with acanthosis, as known from psoriatic skin. [56][57][58]71 Established HS lesions contain massive immune cell infiltrates.…”

Epidermal Stem Cells in Hair Follicle Cycling and Skin Regeneration: A View From the Perspective of Inflammation

“…In the late stages of wound healing, Wnt ligands paradoxically induced fibrotic healing, and these ligands are decreased in WIHN + wounds. A similar process occurs in humans (Gay et al, 2020), where wounds lack WIHN and commonly heal with a cosmetic defect. Thereby, the role of Wnt ligands in wound healing is controversial: on the one hand, they can promote WIHN, which prevents scar formation and causes skin restoration; on the other hand, chronic expression of such ligands can cause wound fibrosis.…”

“…Surprisingly, some of these elements demonstrate delayed effects in this respect. For example, macrophages acting in the inflammation phase (Eming et al, 2007) contribute to WIHN, which occurs during the time of the scar remodeling phase (Gay et al, 2020), and re-epithelialization begins in the proliferation phase under the influence of T regs .…”

“…Type III collagen is replaced by type I collagen with the assistance of MMPs secreted by fibroblasts, macrophages, and endothelial cells (Gurtner et al, 2008). In this phase, HF neogenesis begins (Gay et al, 2020).…”