Mechanobiology of Myofibroblast Adhesion in Fibrotic Cardiac Disease Alison K

© 2015. Published by The Company of Biologists Ltd | Journal of Cell Science (2015) 128, 1865-1875 doi:10.1242/jcs.162891 COMMENTARY ARTICLE SERIES: CELL BIOLOGY AND DISEASE Mechanobiology of myofibroblast adhesion in fibrotic cardiac disease Alison K. Schroer1 and W. David Merryman1,* ABSTRACT behavior and phenotype of cardiac cells, which contributes to Fibrotic cardiac disease, a leading cause of death worldwide, manifests maladaptive tissue remodeling (Cuniberti et al., 2006; Merryman as substantial loss of function following maladaptive tissue remodeling. et al., 2006). Therefore, determining how various cardiac cells Fibrosis can affect both the heart valves and the myocardium and respond to changing mechanical environments will aid our is characterized by the activation of fibroblasts and accumulation of understanding of the development of heart disease and potentially extracellular matrix. Valvular interstitial cells and cardiac fibroblasts, the uncover new targets for future therapy (Fig. 1A). cell types responsible for maintenance of cardiac extracellular matrix, Valvular interstitial cells (VICs) and cardiac fibroblasts (CFs) are are sensitive to changing mechanical environments, and their ability to primarily responsible for maintaining the ECM, and are sensitive to sense and respond to mechanical forces determines both normal mechanical forces in addition to chemical cues. Mechanically induced development and the progression of disease. Recent studies have signaling promotes myofibroblast (MyoFB) differentiation of VICs uncovered specific adhesion proteins and mechano-sensitive signaling and CFs, resulting in cells that exhibit increased contractility and pathways that contribute to the progression of fibrosis. Integrins form increased secretion of growth factors and ECM proteins (Fig. 1B) adhesions with the extracellular matrix, and respond to changes in (Tomasek et al., 2002). MyoFBs interact with the local ECM and sense substrate stiffness and extracellular matrix composition. Cadherins tissue forces through transmembrane ECM receptors called integrins. mechanically link neighboring cells and are likely to contribute to fibrotic Upon adhesion to the ECM, integrins recruit intracellular proteins disease propagation. Finally, transition to the active myofibroblast to form a focal adhesion (FA), which links integrins to the actin phenotype leads to maladaptive tissue remodeling and enhanced cytoskeleton and initiates force-dependent signaling. In addition to mechanotransductive signaling, forming a positive feedback loop force transduction from the ECM to the cells, integrins also that contributes to heart failure. This Commentary summarizes recent regulate force transmission from intracellular stress fibers to the local findings on the role of mechanotransduction through integrins and microenvironment (Baker and Zaman, 2010). MyoFBs are identified α α cadherins to perpetuate mechanically induced differentiation and by their expression of -smooth muscle actin ( -SMA), a specialized fibrosis in the context of cardiac disease. cytoskeletal protein that allows for enhanced generation of cellular force (Hinz et al., 2004). These forces are, in turn, transmitted to the KEY WORDS: Cadherin, Integrin, Myofibroblast local microenvironment, altering ECM structure, and substantially affecting tissue mechanics (Petersen et al., 2012). Introduction Intracellular forces are also transmitted to neighboring cells through The heart is a highly dynamic mechanical environment that stretches adherens junctions (AJs), which contain Ca2+-dependent adhesion and contracts over three billion times during the course of the average proteins called cadherins. Classical cadherins form homotypic bonds human life. Proper functioning of cardiac structures is dependent on with cadherins on neighboring cells and mechanically link the their active and passive mechanical properties, and alteration of these cytoskeletal elements of both cells. Different cadherins are found in properties is a hallmark of fibrotic cardiac disease. Given the high various cell types, and major shifts in cell phenotype are often societal cost of heart disease, the mechanisms regulating fibrotic accompanied by a corresponding shift in cadherin expression. disease progression in heart valves and the myocardium have been Neuronal (N)-cadherin is typically expressed in cardiomyocytes extensively studied. In both tissues, inflammation and fibrosis drive (CMs) and quiescent fibroblasts, whereas osteoblast (OB)-cadherin extensive tissue remodeling that significantly impairs cardiac (also known as cadherin-11) is highly expressed in MyoFBs function (Fig. 1A). Inflammation triggers extracellular matrix (Aisagbonhi et al., 2011; Chalpe et al., 2010; Heuberger and (ECM) degradation and the release of profibrotic factors, such as Birchmeier, 2010; Hinz et al., 2004; Li et al., 2012). OB-cadherin angiotensin II (AGT; hereafter referred to as AngII), transforming forms significantly stronger bonds than N-cadherin and is, thus, able growth factor β1 (TGF-β1), and fibroblast growth factor (FGF), that to transmit increased levels of intercellular tension generated by promote accumulation of ECM and fibrosis of the valves and α-SMA in MyoFBs (Hinz et al., 2004; Hutcheson et al., 2013). Recent myocardium (Chen and Frangogiannis, 2013; Mahler and Butcher, studies have revealed new signaling roles for cadherins in addition to 2011). However, drugs targeting these pathways have had limited their structural function (Leckband and de Rooij, 2014). Signaling success, which has been attributed to their failure to address the effectors downstream of cadherins, including β-catenin, undergo a concurrent mechanical signals that play a crucial role in the initiation substantial crosstalk with cytokine and integrin signaling in the and progression of disease (Frangogiannis, 2014). Conditions that regulation of MyoFB differentiation and function (Caraci et al., 2008; favor increased local tissue strains and stresses increase the risk of Charbonney et al., 2011; Xu et al., 2012). developing fibrotic disease in affected structures by altering the This Commentary focuses on mechanotransduction in VICs and CFs during cardiac fibrotic disease, and its effects on the regulation 1Department of Biomedical Engineering, Vanderbilt University, Nashville, of MyoFB differentiation. Mechanotransduction in endothelial cells TN 37212, USA. is certainly relevant to cardiovascular disease and has been *Author for correspondence ([email protected]) described in an excellent recent review (Conway and Schwartz, Journal of Cell Science 1865 COMMENTARY Journal of Cell Science (2015) 128, 1865-1875 doi:10.1242/jcs.162891 A Fig. 1. Relevance of adhesion mechanobiology to Left atrium fibrotic heart disease. (A) Fibrotic disease affects both heart valves and heart myocardium and is characterized Mitral valve Right atrium by changes in the mechanical properties of the ECM (extracellular matrix) and the cellular phenotypes present Tricuspid valve in the tissue. Healthy valves primarily have quiescent Aortic valve fibroblast-like cells called valvular interstial cells (VICs) Right ventricle Left ventricle that are embedded in a stable, organized ECM and Pulmonary valve surrounded by a single layer of valvular endothelial cells (VECs). Similarly, healthy myocardium contains cardiomyocytes (CMs), cardiac fibroblasts (CFs) and lined blood vessels lined with endothelial cells (ECs) that are embedded in stable ECM. Disease can be initiated by Valve leaflet Myocardium acute or chronic cardiac conditions. Inflammation initiates ECM breakdown, accumulation of inflammatory cells and fibroblast-like cells, as well as EndMT, which yields Healthy tissue Healthy endothelial-to-mesenchymal-transformed cells structure (EndMTCs). Inflammation can turn into fibrosis, which is Flexible and characterized by accumulation of stiff ECM and a large functional number of myofibroblasts (MyoFBs) that are derived from VICs, CFs, and EndMTCs. MyoFBs are particularly Disease inititation relevant to disease because they are able to initiate ECM Infllammatiion remodeling and intercellular signaling pathways. (B) The Disease MyoFB phenotype is promoted by combined inputs of progression Fibrosis mechanical and chemical signals that are transduced, Diseased respectively, through integrins and cadherins, and α Fibrotic tissue signaling factor receptors. Increased expression of - pathology SMA in MyoFBs stabilizes, and further activates integrins and cadherins; this increases the generation of intracellular force and actively remodels the ECM. Stiff and MyoFBs also express ECM and growth factors that not dysfunctional only affect themselves but also neighboring cells. Key Inflammatory B cells Calcified Signaling factors nodule ECM Cellular VIC/CF Intracellular Integrins VEC/EC input force ECM ECM-transmitted CM force EndMTC Cellular MyoFB Release output Integrins of signaling factors and ECM components Cadherins 2013), so this aspect will not be discussed in detail. Likewise, conditions with large clinical impacts are perpetuated by active mechanotransduction in CMs is also important to disease remodeling of the ECM by VICs in valves and by CFs in the progression and has been the subject of another recent review myocardium. (McCain and Parker, 2011). The adhesion molecules of particular interest for this Commentary are integrins and cadherins, which Heart valve disease are both relevant to mechanically regulated signaling and force Valve disease affects

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