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The Ski–Zeb2–Meox2 Pathway Provides a Novel Mechanism For ß 2014. Published by The Company of Biologists Ltd | Journal of Cell Science (2014) 127, 40–49 doi:10.1242/jcs.126722 RESEARCH ARTICLE The Ski–Zeb2–Meox2 pathway provides a novel mechanism for regulation of the cardiac myofibroblast phenotype Ryan H. Cunnington1,2,*, Josette M. Northcott2,3,*, Saeid Ghavami1,2, Krista L. Filomeno1,2, Fahmida Jahan2,3, Morvarid S. Kavosh1,2, Jared J. L. Davies1,2, Jeffrey T. Wigle2,3 and Ian M. C. Dixon1,2,{ ABSTRACT which can persist in the myocardium for months (and even years) after the initial pathological insult (Willems et al., 1994). The Cardiac fibrosis is linked to fibroblast-to-myofibroblast myofibroblast is associated with fibrillar collagen deposition, phenoconversion and proliferation but the mechanisms underlying leading to reduced cardiac efficiency and, ultimately, this are poorly understood. Ski is a negative regulator of TGF-b–Smad decompensated heart failure. Initially, increased collagen signaling in myofibroblasts, and might redirect the myofibroblast deposition is beneficial, but when left to persist for years, it can phenotype back to fibroblasts. Meox2 could alter TGF-b-mediated transform healthy myocardium with normal extracellular matrix cellular processes and is repressed by Zeb2. Here, we investigated complement into overtly fibrosed tissue with abnormal expansion whether Ski diminishes the myofibroblast phenotype by de-repressing of the interstitium (Freed et al., 2005). Meox2 expression and function through repression of Zeb2 Fibroblast-to-myofibroblast phenoconversion is marked by expression. We show that expression of Meox1 and Meox2 mRNA increased expression of a-smooth muscle actin (a-SMA) (Darby and Meox2 protein is reduced during phenoconversion of fibroblasts et al., 1990), extra domain A (ED-A) fibronectin (Serini et al., to myofibroblasts. Overexpression of Meox2 shifts the myofibroblasts 1998), and non-muscle myosin heavy chain b (SMemb) into fibroblasts, whereas the Meox2 DNA-binding mutant has no effect (Frangogiannis et al., 2000). Although not well understood, this on myofibroblast phenotype. Overexpression of Ski partially restores process is typically thought of as being a ‘one-way’ pathway. Meox2 mRNA expression levels to those in cardiac fibroblasts. However, Hinz and colleagues have provided data that both Expression of Zeb2 increased during phenoconversion and Ski forward and reverse phenoconversion are possible in these overexpression reduces Zeb2 expression in first-passage cells, depending upon the compressibility of the underlying myofibroblasts. Furthermore, expression of Meox2 is decreased in substrate (Hinz et al., 2001). Still, the molecular mechanisms for scar following myocardial infarction, whereas Zeb2 protein expression fibroblast–myofibroblast inter-conversion have yet to be fully increases in the infarct scar. Thus Ski modulates the cardiac elucidated. myofibroblast phenotype and function through suppression of Zeb2 The canonical TGF-b signaling cascade has been implicated as by upregulating the expression of Meox2. This cascade might an important inducer of phenoconversion. High levels of this regulate cardiac myofibroblast phenotype and presents therapeutic cytokine are associated with cardiac fibrosis (Brooks and Conrad, 2000). The diverse functions of TGF-b necessitate the tight options for treatment of cardiac fibrosis. control of membrane-to-nucleus signal transduction; in particular, KEY WORDS: Myofibroblasts, Heart, Phenotype switch, Fibrosis, levels of the endogenous inhibitors Smad7 and Ski. The proto- TGF-b oncoprotein Ski has a complex set of functions and is linked to skeletal muscle hypertrophy (Sutrave et al., 1990a; Sutrave et al., 1990b), as well as developmental defects in the neural tube and INTRODUCTION cranial mesenchyme (Berk et al., 1997). Ski binds to R-Smad Fibroblast-to-myofibroblast phenoconversion in the heart is a crucial proteins (Sun et al., 1999; Suzuki et al., 2004; Ueki and Hayman, event in the onset of many cardiovascular diseases. Cardiac 2003; Xu et al., 2000) and might inhibit TGF-b-mediated effects fibroblasts are an understudied cell, despite the fact that they through both nuclear and cytosolic mechanisms (Akiyoshi et al., constitute the majority of cells in the heart (Weber and Brilla, 1991). 1999; Ferrand et al., 2010; Nagata et al., 2006; Suzuki et al., These relatively quiescent cells reside in the cardiac interstitium and 2004). We have previously demonstrated the anti-fibrotic and synthesize cardiac fibrillar collagen types (e.g. types I and III), as anti-contractile effects of overexpression of Ski in TGF-b1- well as the majority of other extracellular matrix proteins. stimulated primary cardiac myofibroblasts, and have shown these Cardiac stress and injury both induce differentiation of inhibitory effects to be orchestrated at the nuclear level fibroblasts into hypersecretory and contractile myofibroblasts, (Cunnington et al., 2011). Mesenchyme homeobox 2 (Meox2, also known as growth arrest specific homeobox protein, Gax) and Meox1 comprise the 1Department of Physiology, University of Manitoba, Winnipeg, MB R3E 0J9, Meox family of homeodomain proteins. Meox1 and Meox2 Canada. 2Institute of Cardiovascular Sciences, University of Manitoba, Winnipeg, MB R3E 0J9, Canada. 3Department of Biochemistry and Medical Genetics, proteins share 95% sequence identity within the homeodomain University of Manitoba, Winnipeg, MB R3E 0J9, Canada. region, but are otherwise highly divergent (Douville et al., 2011). *These authors contributed equally to this work Both Meox1 and Meox2 are required for proper bone and muscle {Author for correspondence ([email protected]) formation in developing mouse embryos (Mankoo et al., 1999; Mankoo et al., 2003). Meox2 expression is decreased by mitogen Received 7 January 2013; Accepted 1 October 2013 stimulation of vascular smooth muscle cells (Gorski et al., 1993) Journal of Cell Science 40 RESEARCH ARTICLE Journal of Cell Science (2014) 127, 40–49 doi:10.1242/jcs.126722 and in mechanically damaged arteries (Weir et al., 1995), fibroblast-to-myofibroblast phenoconversion through the indicating that Meox2 expression is sensitive to a range of differential expression of Ski, Zeb2 and Meox2 proteins. stimuli. Meox2 could enhance TGF-b-mediated inhibition of cell proliferation (Valcourt et al., 2007) or, conversely, might block RESULTS TGF-b-induced epithelial-to-mesenchymal transition (EMT) Meox1 and Meox2 are downregulated during phenoconversion (Valcourt et al., 2007). Meox2 expression is repressed by the Marker proteins frequently used to monitor fibroblast-to- Zeb2 protein [also called Smad-interacting protein 1 (Sip1 or myofibroblast phenoconversion include an increase in Zfhx1b)], a zinc-finger E-box binding protein (Chen et al., 2010). expression of a-SMA (Darby et al., 1990), ED-A fibronectin Zeb2 expression itself has been shown to be positively regulated (Serini et al., 1998) and SMemb (Frangogiannis et al., 2000). by TGF-b signaling during EMT (Comijn et al., 2001). Myofibroblasts in the infarct scar can arise from a range of In this study, we provide data to support a novel mechanism different processes, e.g. fibroblast migration (Gabbiani, 1996), through which Ski regulates the cardiac fibroblast phenotype. differentiation of bone marrow progenitor cells (Mo¨llmann et al., We show for the first time that both Meox1 and Meox2 are 2006; van Amerongen et al., 2008) and EMT (van Tuyn et al., downregulated during fibroblast-to-myofibroblast phenoconversion, 2007; Zhou et al., 2010). Because Meox2 is associated with and that overexpression of Ski can rescue Meox2 expression. inhibition of TGF-b1-induced EMT (Valcourt et al., 2007), we Moreover, our data establish a link between increased Meox2 examined the potential link between Meox2 and induction of the expression and a reduction of the myofibroblast phenotype. Finally, myofibroblast phenotype in rat primary cardiac fibroblasts, and we identify a putative signaling cascade that might modulate in first and second passage myofibroblasts. To our knowledge, Fig. 1. The role of Meox1 and Meox2 in cardiac fibroblast-to-myofibroblast phenoconversion. (A) Meox1 and Meox2 mRNA levels are reduced during fibroblast-to-myofibroblast differentiation. RNA was harvested from P0, P1 and P2 cells and used for qPCR. GAPDH primers served as a control for loading. The data shown were obtained from n53 independent experiments. *P,0.005. (B) Primary fibroblasts (P0) and first (P1) and second (P2) passage myofibroblasts were isolated, total protein prepared, and Meox2 protein expression examined by western blot using a-tubulin as a loading control. Representative western blots for Meox2 and a-tubulin protein expression are shown above the histograms for Meox2 protein expression. The data shown are from n53 independent experiments; *P,0.01 versus P0. Error bars represent s.e. (C) Cryosections of 4-week post-MI rat heart tissue were stained for Meox2 (green) and Vimentin (red) with DAPI nuclear stain (blue). Images are representative of n53 hearts. Journal of Cell Science 41 RESEARCH ARTICLE Journal of Cell Science (2014) 127, 40–49 doi:10.1242/jcs.126722 Meox1, which is closely related to Meox2, has not been implicated Meox2, but not Meox1, overexpression diminishes the in EMT or TGF-b1 signaling. Therefore, we also examined its myofibroblast phenotype putative role in fibroblast-to-myofibroblast phenoconversion. We Because expression of Meox1 and Meox2 mRNA is downregulated observed a 96% and 99% downregulation of Meox2 mRNA during
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