Abstract
Upon cardiac pathological conditions such as ischemia, microenvironmental changes instruct a series of cellular responses that trigger cardiac fibroblasts-mediated tissue adaptation and inflammation. A comprehensive model of how early environmental changes may induce cardiac fibroblasts (CF) pathological responses is far from being elucidated, partly due to the lack of approaches involving complex and simultaneous environmental stimulation. Here, we provide a first analysis of human primary CF behavior by means of a multi-stimulus microdevice for combined application of cyclic mechanical strain and controlled oxygen tension. Our findings elucidate differential human CFs responses to different combinations of the above stimuli. Individual stimuli cause proliferative effects (PHH3+ mitotic cells, YAP translocation, PDGF secretion) or increase collagen presence. Interestingly, only the combination of hypoxia and a simulated loss of contractility (2% strain) is able to additionally induce increased CF release of inflammatory and pro-fibrotic cytokines and matrix metalloproteinases.
Highlights
When supply of oxygen and nutrients to the myocardium is critically reduced, a complex tissue response takes place: within hours tissue necrosis and death of contractile cardiac myocytes occurs in the infarcted area giving rise to an inflammatory phase that recruits immune cells and activates quiescent cardiac fibroblasts (CFs); within a few days a proliferative phase begins, where activated CFs invade the infarcted area and contribute to degrading and replacing the extra-cellular matrix with a collagen-based scar; within weeks the maturation of the fibrotic scar is completed (Frangogiannis, 2014; Heusch et al, 2014)
We quantified the expression of matrix metalloproteinases (MMP)-2 and MMP-3 in cell culture supernatants, two enzymes expressed by CFs during cardiac remodeling (Fan et al, 2012)
We report that culturing CFs at NX levels does not induce significant changes in collagen I presence
Summary
When supply of oxygen and nutrients to the myocardium is critically reduced (ischemia), a complex tissue response takes place: within hours tissue necrosis and death of contractile cardiac myocytes occurs in the infarcted area giving rise to an inflammatory phase that recruits immune cells and activates quiescent cardiac fibroblasts (CFs); within a few days a proliferative phase begins, where activated CFs invade the infarcted area and contribute to degrading and replacing the extra-cellular matrix with a collagen-based scar; within weeks the maturation of the fibrotic scar is completed (Frangogiannis, 2014; Heusch et al, 2014). Cellular and molecular events such as excessive proliferation of CFs, phenotypic switch of CFs, high levels of inflammatory cytokines and humoral factors, unbalanced synthesis of extracellular matrix (ECM) proteins and matrix metalloproteinases (MMP)mediated degradation of ECM are generally regarded as hallmarks of early fibrotic tissue response (Fan et al, 2012; Krenning et al, 2010; Porter and Turner, 2009; Shinde and Frangogiannis, 2014) This essential process maintains tissue integrity, it often leads to excessive and adverse CFs remodeling of non-infarcted areas (Fan et al, 2012; Kania et al, 2009; Talman and Ruskoaho, 2016) associated with cardiac dysfunction and increased mortality (Okada et al, 2005)
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