INTRODUCTION Scar formation and tissue regeneration are

INTRODUCTION Scar formation and tissue regeneration are opposite results of the wound healing process. Although fibrosis is more common after skin injury, full skin regeneration results in complete replacement of adnexa and function. Examples of tissue regeneration in mammalian systems include annual regeneration in deer antlers, ear regeneration following tag removal in mice and rabbits, and regeneration of amputated digit tips and liver regeneration in both mice and humans (; ; ; Jia, 2011). In skin, fully described and characterized de novo hair follicle neogenesis that is dependent on Wnt signaling after full-thickness wounding in mice. These regenerated hair follicles establish a stem cell population, express hair follicle differentiation markers, produce a functional hair shaft, successfully transition through all phases of the hair cycle, and include associated structures, such as sebaceous glands (). However, what triggers mammalian regeneration is not completely understood. Determining which factors regulate this process may reveal mechanisms and lead to specifically designed therapies to enhance regeneration. Prostaglandins (PGs) are lipid signaling molecules enzymatically derived from arachidonic mk2206 that function in both an autocrine and paracrine manner to regulate broad functions. Prostaglandin-endoperoxidase synthase 2 (Ptgs2; prostaglandin G/H synthase, cyclooxygenase 2) is a key enzyme in the PG biosynthesis pathway, converting arachidonic acid to PG H2, from which prostacyclin, thromboxane A2, PGD2, PGE2, and PGF2α are produced by specific synthase enzymes. Individual PGs often have opposing biological effects. For example, in the lung, PGE2 causes relaxation, whereas PGD2 causes contraction of bronchial muscle (). Recent studies demonstrate that PGs regulate hair growth. Increases in PG levels within the epidermis through overexpression of Ptgs2 cause alopecia and sebaceous hyperplasia, and may or may not cause a predisposition to squamous cell tumors (; ; ). Prostaglandin D2, E2, and F2α metabolism and signaling proteins are expressed in the hair follicle (; ). The Food and Drug Administration (FDA)-approved PGF2α analog, bimatoprost is used clinically to enhance hair growth of human eyelashes (Johnstone and Albert, 2002). PGE2 and PGF2α enhance hair growth in mice (; ). In contrast, PGD2 inhibits hair growth in humans and mice (), demonstrating the opposing functions of PGs. PGD2 levels are significantly increased in bald scalp compared with haired scalp of patients with male pattern hair loss. Moreover, topically applied exogenous PGD2 inhibits the hair growth of mice and explants of human hair follicles through the PGD2–GPR44 signaling pathway (). These results imply a regulatory network in hair follicles wherein PGD2 inhibits, whereas PGE2/F2α promote, hair follicle function. PGs are key inflammatory mediators involved in wound healing; however, no study has examined their role in skin regeneration. We hypothesized that, given their presence during wound healing, PGs would affect wound-induced hair follicle neogenesis (WIHN). With reports of PGE2 promoting regeneration (), we further hypothesized that PGD2 would inhibit regeneration. In this study, we characterize the fluctuations of PGs throughout wound healing and demonstrate that levels of PGD2 are inversely correlated with WIHN. Furthermore, we define an alternatively spliced transcript variant of lipocalin-type PGDsynthase (Ptgds, L-pgds) that correlates with the regeneration phenotype among several strains of mice. We demonstrate that PGD2 inhibits hair follicle regeneration through the G-protein-coupled receptor Gpr44 (DP-2).
RESULTS
DISCUSSION Wound healing usually results in inadequate tissue repair by scarring or fibrosis. In some cases, however, tissue regeneration can occur. Our understanding of the control of wound scarring versus tissue regeneration is incomplete. The contribution of inflammatory mediators, including PGs, during the wound healing process is well established. PG functions during tissue regeneration are less studied, but it is known that PGE2 can stimulate liver regeneration (). Given the demonstration of increased hair growth by PGF2α and PGE2 (; ), and decreased hair growth by PGD2 (), we hypothesized that these PGs may be important in regulating hair neogenesis in WIHN. Normal hair growth is regulated by transition between catagen, anagen, and telogen phases of the hair cycle. During anagen, the hair follicle partially regenerates, suggesting that the pathways that control the hair regeneration cycle may also control hair follicle neogenesis. In this article, we demonstrated that PGD2 correlates with decreased follicle regeneration after wounding, that PGD2 has the capacity to inhibit follicle regeneration, and that the mechanism of this inhibition is through the Gpr44 receptor.