TGF-β-induced differentiation into myofibroblasts involves specific regulation of two MKL1 isoforms

Scharenberg, Matthias A.; Pippenger, Benjamin E.; Sack, Ragna; Zingg, Dominik; Ferralli, Jacqueline; Schenk, Susanne; Martin, Ivan; Chiquet‐Ehrismann, Ruth

doi:10.1242/dev.109546

Cited by 20 publications

(23 citation statements)

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“…Approaches to relax myofibroblasts include: (1) specific interference with α-SMA in contractile stress fibers ; (2) inhibition of the Rho/Rho-associated kinase pathway that acts on myosin activity (Bond et al, 2011;Huang et al, 2011;Zhou et al, 2013); (3) interference with megakaryoblastic leukemia factor 1 (MKL1), also named myocardinrelated transcription factor (MRTF) that links mechanical stress via the polymerization state of actin to the transcriptional activity of muscle-cell genes in various myofibroblast precursor cells (Crider et al, 2011;Luchsinger et al, 2011;Scharenberg et al, 2014;Small et al, 2010;, and (4) interfering with YAP/TAZ transcription factors that mediate mechanoresponses (Halder et al, 2012) and positively regulate myofibroblast activation (Calvo et al, 2013;Liu et al, 2014;Speight et al, 2013;Talele et al, 2015). Rho kinase inhibitors were also used to inhibit myofibroblast activation from tenocytes, keratocytes, trabecular meshwork cells, and stromal fibroblasts (Anderson et al, 2004;Chen et al, 2009;Meyer-ter-Vehn et al, 2006;Pattabiraman et al, 2014;Petroll and Lakshman, 2015;Yamamoto et al, 2012).…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

Myofibroblasts

Hinz¹

2016

Experimental Eye Research

362

341

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Myofibroblasts are activated in response to tissue injury with the primary task to repair lost or damaged extracellular matrix. Enhanced collagen secretion and subsequent contraction - scarring - are part of the normal wound healing response and crucial to restore tissue integrity. Due to myofibroblasts ability to repair but not regenerate, accumulation of scar tissue is always associated with reduced organ performance. This is a fair price to pay by the body for not falling apart. Whereas myofibroblasts typically vanish after successful repair, dysregulation of the normal repair process can lead to persistent myofibroblast activation, for instance by chronic inflammation or mechanical stress in the tissue. Excessive repair leads to the accumulation of stiff collagenous ECM contractures - fibrosis - with dramatic consequences for organ function. The clinical need to terminate detrimental myofibroblast activities has stimulated researchers to answer a number of essential questions: where do myofibroblasts come from, what are the factors leading to their activation, how do we discriminate myofibroblasts from other cells, what is the molecular basis for their contractile activity, and how can we stop or at least control them? This article reviews the current state of the myofibroblast literature by emphasizing their role in ocular repair and fibrosis. It appears that although the eye is quite an extraordinary organ, ocular myofibroblasts behave or misbehave just like their siblings in other organs.

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Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

Myofibroblasts

Hinz¹

2016

Experimental Eye Research

362

341

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“…30 Previous studies suggested that MRTF-A translocation into nucleus may contribute to myofibroblast differentiation in human lung and cardiac fibrosis. 31,32 MRTF-A mediated gene expression has been shown to be mediated by the activation of RhoA/ROCK pathway. 17 With the growing evidence available in cellular and animal models, we hypothesized that RhoA/ROCK2 constitute an intrinsic mechanotransduction pathway that could transduce and convert mechanical stimulation to a signal that promoted scleral a-SMA expression in a mammalian myopia model.…”

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confidence: 99%

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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“…It has therefore been hypothesized that the phenotypic conversion of CFs into specialized myofibroblasts is a critical process mediating cardiac remodeling. Previous studies show that TGF-1 is the most potent stimulator of the activation and differentiation of fibroblasts into myofibroblasts [17]. After fibroblast maturation to myofibroblasts, an increase in the synthesis and secretion of fibronectin is observed.…”

Section: Discussionmentioning

confidence: 94%

Hydrogen sulfide suppresses transforming growth factor-β1-induced differentiation of human cardiac fibroblasts into myofibroblasts

Zhang

Wang

et al. 2015

Sci. China Life Sci.

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In heart disease, transforming growth factor-β1 (TGF-β1) converts fibroblasts into myofibroblasts, which synthesize and secrete fibrillar type I and III collagens. The purpose of the present study was to investigate how hydrogen sulfide (H2S) suppresses TGF-β1-induced differentiation of human cardiac fibroblasts to myofibroblasts. Human cardiac fibroblasts were serum-starved in fibroblast medium for 16 h before exposure to TGF-β1 (10 ng mL(-1)) for 24 h with or without sodium hydrosulfide (NaHS, 100 µmol L(-1), 30 min pretreatment) treatment. NaHS, an exogenous H2S donor, potently inhibited the proliferation and migration of TGF-β1-induced human cardiac fibroblasts and regulated their cell cycle progression. Furthermore, NaHS treatment led to suppression of fibroblast differentiation into myofibroblasts, and reduced the levels of collagen, TGF-β1, and activated Smad3 in TGF-β1-induced human cardiac fibroblasts in vitro. We therefore conclude that H2S suppresses TGF-β1-stimulated conversion of fibroblasts to myofibroblasts by inhibiting the TGF-β1/Smad3 signaling pathway, as well as by inhibiting the proliferation, migration, and cell cycle progression of human cardiac myofibroblasts. These effects of H2S may play significant roles in cardiac remodeling associated with heart failure.

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TGF-β-induced differentiation into myofibroblasts involves specific regulation of two MKL1 isoforms

Cited by 20 publications

References 1 publication

Myofibroblasts

Myofibroblasts

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

Hydrogen sulfide suppresses transforming growth factor-β1-induced differentiation of human cardiac fibroblasts into myofibroblasts

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