Loss of PPARγ expression by fibroblasts enhances dermal wound closure

Abstract

BackgroundPeroxisome proliferator-activated receptor (PPAR)γ may be a key regulator of connective tissue deposition and remodeling in vivo. PPARγ expression is reduced in dermal fibroblasts isolated from fibrotic areas of scleroderma patients; PPARγ agonists suppress the persistent fibrotic phenotype of this cell type. Previously, we showed that loss of PPARγ expression in fibroblasts resulted in enhanced bleomycin-induced skin fibrosis. However, whether loss of PPARγ expression in skin fibroblasts affects cutaneous tissue repair or homeostasis is unknown.ResultsMice deleted for PPARγ in skin fibroblasts show an enhanced rate of dermal wound closure, concomitant with elevated phosphorylation of Smad3, Akt and ERK, and increased expression of proliferating cell nuclear antigen (PCNA), collagen, α-smooth muscle actin (α-SMA) and CCN2. Conversely, dermal homeostasis was not appreciably affected by loss of PPARγ expression.ConclusionPPARγ expression by fibroblasts suppresses cutaneous tissue repair. In the future, direct PPARγ antagonists and agonists might be of clinical benefit in controlling chronic wounds or scarring, respectively.

Thrombospondin-1 mediates oncogenic Ras–induced senescence in premalignant lung tumors

“…However, in the adult lung fibroblasts used in our study, we showed that endogenous Kras G12D increased pERK and induced premature cell senescence. The discrepancy between MEFs and adult lung fibroblasts in response to the expression of endogenous Kras G12D may be due to cell-intrinsic differences (47)(48)(49)(50)(51). We also demonstrated that TSP-1 interacted directly with pERK, implicating the necessity of TSP-1 for a MAPK-dependent senescence response.…”

The Contribution of Peroxisome Proliferator–Activated Receptor Gamma to Cutaneous Wound Healing

“…8 Although PPAR-c knockout mouse embryonic fibroblasts display elevated constitutive Smad3 phosphorylation and collagen production, 26 PPAR-c knockout mouse adult dermal fibroblasts in vivo and in vitro show neither elevated Smad3 phosphorylation nor collagen production. 24,25 However, PPAR-c knockout mouse adult dermal fibroblasts instead show enhanced sensitivity to exogenously added TGF-b, bleomycin, and injury in terms of both enhanced phosphorylation of Smad3 and expression of collagen/a-SMA mRNAs. 24,25 Collectively, these data strongly suggest that, in adult mice, endogenous PPAR-c suppresses fibrogenic responses by impairing cellular responses to TGF-b (Fig.…”

“…23 Mice harboring a fibroblast-specific deletion for PPAR-c displayed an enhanced susceptibility to bleomycin-induced skin scleroderma, as well as an increased rate of cutaneous tissue repair. 24,25 Dermal homeostasis, however, is unaffected in PPAR-c knockout mice 25 suggesting that loss of endogenous PPAR-c is insufficient to induce fibroproliferative responses in vivo; instead the role endogenous PPAR-c is to properly suppress a fibrogenic program. In this regard, it is interesting to note that although PPAR-c expression is reduced in scleroderma fibroblasts 23 and PPAR-c is induced in skin keratinocytes in response to tissue injury, PPAR-c expression is unaltered in the dermis of injured mice.…”

Fibroblasts maintained in 3 dimensions show a better differentiation state and higher sensitivity to estrogens

“…In immortalized ERE-LUC-fibroblasts kept in our dynamic 3D culture conditions, genes related to cell cycle, proliferation, cytoskeleton, migration, adhesion and motility were all down-regulated as well as oncogene expression and inflammatory cytokines. Among the induced genes, the pro-apoptotic Bid gene, MMP10 (stromelysin2), an important metalloprotein usually synthesized by keratinocytes involved in skin wound healing and cellular and the PPARg nuclear receptor which plays a role in the regulation of the pro-fibrotic response and inhibits TGF-beta induced collagen gene expression (Ghosh et al, 2004;Sha et al, 2012).…”