Hic-5 Promotes the Hypertrophic Scar Myofibroblast Phenotype by Regulating the TGF-β1 Autocrine Loop

Dabiri, Ganary; Tumbarello, David A; Turner, Christopher E; Van De Water, Livingston
October 2008
Journal of Investigative Dermatology;Oct2008, Vol. 128 Issue 10, p2518
Academic Journal
Following severe traumatic or thermal injury to the dermis, hypertrophic scars (HTSs) often develop in humans. These scar fibroblasts (hypertrophic scar fibroblasts (HTSFs)) retain the myofibroblast phenotype persistently, rather than transiently as in acute wounds. These pathogenic myofibroblasts constitutively express smooth-muscle cell α-actin (SMAA), deposit an excessive amount of extracellular matrix (ECM) proteins, are highly contractile, and stably display large focal adhesions. Increasing evidence supports a mechanism in which autocrine production and activation of transforming growth factor-β1 (TGF-β1) are required to maintain the pathogenic myofibroblast phenotype. We recently reported that Hic-5, a focal adhesion protein that is upregulated by TGF-β1, is expressed persistently in HTSF compared to normal adult fibroblasts (NADFs). We now find that Hic-5 is an important regulator of the constitutive myofibroblast phenotype in HTSFs. Silencing the expression of Hic-5 in HTSFs with specific siRNAs dramatically reduces TGF-β1 production, decreases the generation of supermature focal adhesions reduces expression of SMAA and decreases collagen contraction and ECM synthesis. Our findings demonstrate that Hic-5 is an essential component of the mechanism regulating autocrine production of TGF-β1 and the resulting pathogenic myofibroblast phenotype.Journal of Investigative Dermatology (2008) 128, 2518–2525; doi:10.1038/jid.2008.90; published online 10 April 2008


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