Prostaglandin E2 differentially modulates human fetal and adult dermal fibroblast migration and contraction: implication for wound healing.
Cyclooxygenase-2 is up-regulated shortly after dermal injury and it has been shown to have important activity during the repair process. Its main product in the skin, prostaglandin E2 (PGE2), modulates both inflammatory and fibrotic processes during wound healing and partially dictates the overall outcome of wound healing. PGE2 signaling has been shown to be altered during fetal wound healing. This study was designed to examine the mechanism(s) by which PGE2 regulates fibroblast migration and contraction and to determine whether these mechanisms are conserved in fetal-derived dermal fibroblasts. Fetal and adult dermal fibroblasts express all four PGE2 receptors. PGE2 inhibits fetal and adult fibroblast migration in a dose-dependent manner through the EP2/EP4-cAMP-protein kinase A pathway. However, fetal fibroblasts appear to be refractory to this effect, requiring a 10-fold higher concentration of PGE2 to achieve a similar degree of inhibition as adult fibroblasts. Inhibition of adult fibroblast migration correlated with disruption of the actin cytoskeleton. In contrast, PGE2 or a cAMP analog did not disrupt the actin cytoskeleton of fetal dermal fibroblasts. These findings were extended using a modified free-floating, fibroblast-populated collagen lattice (FPCL) contraction assay designed to measure fibroblast contraction. PGE2-inhibited FPCL contraction by adult fibroblasts, but fetal fibroblasts exhibited higher rates of FPCL contraction and a blunted response to exogenous modulation by PGE2 or a cyclase activator (forskolin). These findings indicate that fetal dermal fibroblasts are partially refractory to the effects of PGE2, a major inflammatory mediator associated with dermal wound healing. This effect may have significant and specific relevance to the scarless fetal wound-healing phenotype.
Sandulache
Vlad C
VC
Department of Pediatric Otolaryngology, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
Parekh
Aron
A
Li-Korotky
Ha-Sheng
HS
Dohar
Joseph E
JE
Hebda
Patricia A
PA
D000328:Adult; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects; D002921:Cicatrix / Q000503:physiopathology; D000242:Cyclic AMP / Q000378:metabolism; D020405:Dermis / Q000166:cytology / Q000378:metabolism; D015232:Dinoprostone / Q000494:pharmacology*; D005333:Fetus / Q000166:cytology; D005347:Fibroblasts / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D012333:RNA, Messenger / Q000032:analysis; D011982:Receptors, Prostaglandin / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects* / Q000502:physiology*
D012333:RNA, Messenger; D011982:Receptors, Prostaglandin; D000242:Cyclic AMP; D015232:Dinoprostone