A Role of Myocardin Related Transcription Factor-A (MRTF-A) in Scleroderma Related Fibrosis

Xu, Shiwen; Stratton, Richard; Nikitorowicz-Buniak, Joanna; Ahmed-Abdi, B; Ponticos, Markella; Denton, Christopher P.; Abraham, David; Takahashi, Ayuko; Suki, Bélâ; Layne, Matthew D.; Lafyatis, Robert; Smith, Barbara D.

doi:10.1371/journal.pone.0126015

Cited by 83 publications

(57 citation statements)

References 86 publications

(111 reference statements)

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“…We infer from our data that Hic-5-dependent sustained development of stress fibers in pathogenic myofibroblasts supports persistent MRTF-A localization, thereby perpetuating the myofibroblast phenotype. Consistent with this notion is the observation that small molecules that promote MRTF-A function result in quicker wound closure (Velasquez et al, 2013), whereas MRTF-A inhibitors can reduce fibrotic markers in scleroderma mouse models Shiwen et al, 2015).…”

Section: Discussionmentioning

confidence: 88%

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

Varney

Betts

Zheng

et al. 2016

Journal of Cell Science

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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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Section: Discussionmentioning

confidence: 88%

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

Varney

Betts

Zheng

et al. 2016

Journal of Cell Science

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“…MRTF-A interactions with YAP have generated substantial interest in the nuclear localization patterns of MRTF-A (58-60), but to date nearly all investigations that test stiffness variations have analyzed only two distinct values (61,62). Leveraging our gradient system, we analyzed expression patterns of MRTF-A and MRTF-B in hASCs plated for 24 h on 2.9-kPa/mm hydrogels and found that although MRTF-B localization was independent of stiffness ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Stem cell migration and mechanotransduction on linear stiffness gradient hydrogels

Hadden

Young

Holle

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

402

323

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The spatial presentation of mechanical information is a key parameter for cell behavior. We have developed a method of polymerization control in which the differential diffusion distance of unreacted cross-linker and monomer into a prepolymerized hydrogel sink results in a tunable stiffness gradient at the cell-matrix interface. This simple, low-cost, robust method was used to produce polyacrylamide hydrogels with stiffness gradients of 0.5, 1.7, 2.9, 4.5, 6.8, and 8.2 kPa/mm, spanning the in vivo physiological and pathological mechanical landscape. Importantly, three of these gradients were found to be nondurotactic for human adipose-derived stem cells (hASCs), allowing the presentation of a continuous range of stiffnesses in a single well without the confounding effect of differential cell migration. Using these nondurotactic gradient gels, stiffness-dependent hASC morphology, migration, and differentiation were studied. Finally, the mechanosensitive proteins YAP, Lamin A/C, Lamin B, MRTF-A, and MRTF-B were analyzed on these gradients, providing higher-resolution data on stiffness-dependent expression and localization. mechanobiology | stem cell migration | stem cell differentiation | extracellular matrix | stiffness

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“…A previous study indicated that type I collagen synthesis depended on MRTF-A activation. 58 Therefore, MRTF-A was activated and translocated to the nucleus under 4% strain stimulation, and then induced collagen synthesis. However, the results of in vitro study were not consistent with the findings in vivo.…”

Section: Discussionmentioning

confidence: 97%

The Role of the RhoA/ROCK Signaling Pathway in Mechanical Strain-Induced Scleral Myofibroblast Differentiation

Yuan

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Biomechanical properties changes and a-smooth muscle actin (a-SMA) overexpression are involved in myopia scleral remodeling. However, interactions between altered tissue biomechanics and cellular signaling that sustain scleral remodeling have not been well defined. We determine the mechanisms of mechanotransduction in the regulation of a-SMA expression during myopia scleral remodeling.METHODS. Guinea pigs were used to establish a form-deprivation myopia (FDM) model. Protein profiles in myopic sclera were examined using tandem mass spectrometry. Ras homolog gene family member A (RhoA) and a-SMA expressions were confirmed using quantitative (q) RT-PCR and Western blotting. Scleral fibroblasts were cultured and subjected to 4% cyclic strain. Levels of RhoA, rho-associated protein kinase-2 (ROCK2), myocardin-related transcription factor-A (MRTF-A), serum response factor (SRF), and a-SMA were determined by qRT-PCR and Western blotting in groups with or without the RhoA siRNA or ROCK inhibitor Y27632. MRTF-A and a-SMA were evaluated by confocal immunofluorescent microscopy and myofibroblasts were enumerated using flow cytometry.RESULTS. mRNA and protein levels of RhoA and a-SMA were significantly increased in the FDM eyes after 4 weeks of form-deprivation treatment. The 4% static strain increased expressions of RhoA, ROCK2, MRTF-A, SRF, and a-SMA as well as nuclear translocalization of MRTF-A in scleral fibroblasts compared to those without strain stimulation. Additionally, the percentage of myofibroblasts increased after strain stimulation. Conversely, inhibition of RhoA or ROCK2 reversed the strain-induced a-SMA expression and myofibroblast ratio.CONCLUSIONS. Mechanical strain activated RhoA signaling and scleral myofibroblast differentiation. Strain also mediated myofibroblast differentiation via the RhoA/ROCK2-MRTF-A/SRF pathway. These findings provided evidence for a mechanical strain-induced RhoA/ROCK2 pathway that may contribute to myopia scleral remodeling.

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A Role of Myocardin Related Transcription Factor-A (MRTF-A) in Scleroderma Related Fibrosis

Cited by 83 publications

References 86 publications

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

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

Stem cell migration and mechanotransduction on linear stiffness gradient hydrogels

The Role of the RhoA/ROCK Signaling Pathway in Mechanical Strain-Induced Scleral Myofibroblast Differentiation

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