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

SD Varney, CB Betts, R Zheng, L Wu… - Journal of cell …, 2016 - journals.biologists.com
SD Varney, CB Betts, R Zheng, L Wu, B Hinz, J Zhou, L Van De Water
Journal of cell science, 2016journals.biologists.com
How mechanical cues from the extracellular environment are translated biochemically to
modulate the effects of TGF-β 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-β. 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 …
Abstract
How mechanical cues from the extracellular environment are translated biochemically to modulate the effects of TGF-β 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-β. 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-β. 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-β.
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