Prostaglandin D2 Inhibits Wound-Induced Hair Follicle Neogenesis through the Receptor, Gpr44

Abstract

Prostaglandins (PGs) are key inflammatory mediators involved in wound healing and regulating hair growth; however, their role in skin regeneration after injury is unknown. Using wound-induced hair follicle neogenesis (WIHN) as a marker of skin regeneration, we hypothesized that PGD2 decreases follicle neogenesis. PGE2 and PGD2 were elevated early and late respectively during wound healing. The levels of WIHN, lipocalin-type prostaglandin D2 synthase (Ptgds) and its product PGD2 each varied significantly among background strains of mice after wounding and all correlated such that the highest Ptgds and PGD2 levels were associated with the lowest amount of regeneration. Additionally, an alternatively spliced transcript variant of Ptgds missing exon 3 correlated with high regeneration in mice. Exogenous application of PGD2 decreased WIHN in wild type mice and PGD2 receptor Gpr44 null mice showed increased WIHN compared to strain-matched control mice. Furthermore, Gpr44 null mice were resistant to PGD2-induced inhibition of follicle neogenesis. In all, these findings demonstrate that PGD2 inhibits hair follicle regeneration through the Gpr44 receptor and imply that inhibition of PGD2 production or Gpr44 signaling will promote skin regeneration.

dsRNA Released by Tissue Damage Activates TLR3 to Drive Skin Regeneration

“…In studies characterizing molecular mechanisms of WIHN, we and others observed significant differences in the regenerative capacity of various mouse strains when visualized by c onfocal s canning l aser m icroscopy (CSLM) (Fig. 1A) (Fan et al, 2011; Ito et al, 2007; Nelson et al, 2013). To identify factors that may initiate regeneration, we compared gene expression profiles from healed wounds of mice with high and low regenerative capacity using C57BL/6 and our mixed background strain of mice (C57BL/6 x FVB x SJL).…”

“…We and others found that the capacity to regenerate skin and hair follicles, a process termed w ound- i nduced h air n eogenesis (WIHN), varies greatly among different strains of mus musculus (Fig. 1) (Ito et al, 2007; Nelson et al, 2013). While large variation between strains is challenging and requires very careful strain-matched and transgenic controls for all experiments, it is also an opportunity to explore the causes of this biological variation.…”

“…While originally described in the 1940s, WIHN has recently been characterized in morphogenetic and molecular detail (Breedis, 1954; Gay et al, 2013; Ito et al, 2007; Kligman and Strauss, 1956; Myung et al, 2013; Nelson et al, 2013). Following complete excision of skin down to fascia, wounds on the backs of mice heal through initial contracture and then re-epithelialization.…”

Wound Healing and Skin Regeneration

“…These findings showed that the interplay between immune cells and skin fibroblasts recruited to the wound site is essential to the activation of molecular pathways that promote hair follicle regeneration. On the other hand, another study showed that application of prostaglandin (PGD 2 ), an inflammatory mediator, inhibits hair neogenesis while new hair formation is enhanced in mice that lack a receptor for PGD 2 , GPR44 (Nelson et al 2013). These results suggest that inflammatory mediators involved in wound healing have the ability to modulate hair follicle regeneration in the wound area.…”

Topical Diclofenac 3% Gel for Actinic Keratosis May Induce Terminal Hair in Male Androgenetic Alopecia: A Report of Three Cases

“…Frequently, as it occurs in other organs, different PGs have opposing biological effects. In the case of the hair follicle, PGD 2 inhibits hair growth, whereas PGE 2 and PGF 2 α enhance it (4,6). A recent study found that PGD 2 levels significantly increased in bald scalp compared with haired scalp of patients with AGA (7).…”