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J Dermatol Sci. 2015 Dec;80(3):186-95. doi: 10.1016/j.jdermsci.2015.10.005. Epub 2015 Oct 9.

Ligand-activated PPARδ upregulates α-smooth muscle actin expression in human dermal fibroblasts: A potential role for PPARδ in wound healing.

Author information

1
Department of Animal Biotechnology, Konkuk University, Seoul 143-701, Republic of Korea.
2
Department of Nursing, Semyung University, Chungbuk 390-711, Republic of Korea.
3
Department of Biomedical Science, CHA University, Seongnam, Gyeonggi-Do 463-400, Republic of Korea.
4
Department of Animal Biotechnology, Konkuk University, Seoul 143-701, Republic of Korea. Electronic address: hgseo@konkuk.ac.kr.

Abstract

BACKGROUND:

The phenotypic changes that accompany differentiation of resident fibroblasts into myofibroblasts are important aspects of the wound healing process. Recent studies showed that peroxisome proliferator-activated receptor (PPAR) δ plays a critical role in wound healing.

OBJECTIVE:

To determine whether the nuclear receptor PPARδ can modulate the differentiation of human dermal fibroblasts (HDFs) into myofibroblasts.

METHODS:

These studies were undertaken in primary HDFs using Western blot analyses, small interfering (si)RNA-mediated gene silencing, reporter gene assays, chromatin immunoprecipitation (ChIP), migration assays, collagen gel contraction assays, and real-time PCR.

RESULTS:

Activation of PPARδ by GW501516, a specific ligand of PPARδ, specifically upregulated the myofibroblast marker α-smooth muscle actin (α-SMA) in a time- and concentration-dependent manner. This induction was significantly inhibited by the presence of siRNA against PPARδ, indicating that PPARδ is involved in myofibroblast transdifferentiation of HDFs. Ligand-activated PPARδ increased α-SMA promoter activity in a dual mode by directly binding a direct repeat-1 (DR1) site in the α-SMA promoter, and by inducing expression of transforming growth factor (TGF)-β, whose downstream effector Smad3 interacts with a Smad-binding element (SBE) in another region of the promoter. Mutations in these cis-elements totally abrogated transcriptional activation of the α-SMA gene by the PPARδ ligand; thus both sites represent novel types of PPARδ response elements. GW501516-activated PPARδ also increased the migration and contractile properties of HDFs, as demonstrated by Transwell and collagen lattice contraction assays, respectively. In addition, PPARδ-mediated upregulation of α-SMA was correlated with elevated expression of myofibroblast markers such as collagen I and fibronectin, with a concomitant reduction in expression of the epithelial marker E-cadherin.

CONCLUSION:

PPARδ plays pivotal roles in wound healing by promoting fibroblast-to-myofibroblast differentiation via TGF-β/Smad3 signaling.

KEYWORDS:

Human dermal fibroblast; Myofibroblast; PPARδ; Smad3; α-SMA

PMID:
26481780
DOI:
10.1016/j.jdermsci.2015.10.005
[Indexed for MEDLINE]

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