Hic-5 is required for myofibroblast differentiation by regulating mechanically dependent MRTF-A nuclear accumulation

Scott D. Varney, Courtney B. Betts, Rui Zheng, Lei Wu, Boris Hinz, Jiliang Zhou, Livingston Van De Water

Research output: Contribution to journalArticlepeer-review

49 Scopus citations


How mechanical cues from the extracellular environment are translated biochemically to modulate the effects of TGF-ß on myofibroblast differentiation remains a crucial area of investigation. We report here that the focal adhesion protein, Hic-5 (also known as TGFB1I1), is required for the mechanically dependent generation of stress fibers in response to TGF-ß. Successful generation of stress fibers promotes the nuclear localization of the transcriptional co-factor MRTF-A (also known as MKL1), and this correlates with the mechanically dependent induction of α smooth muscle actin (α-SMA) and Hic-5 in response to TGF-ß. As a consequence of regulating stress fiber assembly, Hic-5 is required for the nuclear accumulation of MRTF-A and the induction of α-SMA as well as cellular contractility, suggesting a crucial role for Hic-5 in myofibroblast differentiation. Indeed, the expression of Hic-5 was transient in acute wounds and persistent in pathogenic scars, and Hic-5 colocalized with α-SMA expression in vivo. Taken together, these data suggest that a mechanically dependent feed-forward loop, elaborated by the reciprocal regulation of MRTF-A localization by Hic-5 and Hic-5 expression by MRTF-A, plays a crucial role in myofibroblast differentiation in response to TGF-ß.

Original languageEnglish (US)
Pages (from-to)774-787
Number of pages14
JournalJournal of Cell Science
Issue number4
StatePublished - 2016


  • Fibrosis
  • Hic-5
  • MRTF-A
  • Mechanotransduction
  • Myofibroblast
  • Wound healing

ASJC Scopus subject areas

  • Cell Biology


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