TGF-beta1 slows the growth of pathogenic myofibroblasts through a mechanism requiring the focal adhesion protein, Hic-5.

Pathogenic scarring is a devastating disorder that impairs normal tissue function after injury. Differentiated myofibroblasts deposit and organize scars over a continuum, from normal to pathogenic, and yet the mechanisms regulating their appearance and disappearance from tissues are enigmatic. We reported previously that key functions of myofibroblasts derived from hypertrophic scars (HTSF) are constitutively activated by an autocrine loop involving transforming growth factor-beta1 (TGF-beta1). We now report that this autocrine induction of TGF-beta1 results in a constitutively high level of Hic-5, which markedly reduces HTSF proliferation relative to normal adult human dermal fibroblasts (NADF) without changing apoptosis. Cyclin D1 and A levels are constitutively lower in HTSF compared to NADF, and the cyclin-dependent kinase inhibitor p21(cip1) is upregulated in HTSF and located in the nucleus. Inhibition of autocrine TGF-beta1 production in HTSF reverses this process, lowering Hic-5 and p21(cip1) levels and increasing replication. Moreover, Hic-5 is partially localized in the nucleus of HTSF, and knocking down Hic-5 with specific siRNAs in these cells results in decreased p21(cip1) levels and a concomitant increase in proliferation. Our findings show that autocrine production of TGF-beta1 upregulates the expression of Hic-5, which is essential for perpetuating the decreased proliferation seen in this pathogenic myofibroblast.