Diverse origins and activation of fibroblasts in cardiac fibrosis

Cardiac fibroblasts (cFBs) have emerged as a heterogenous cell population. Fibroblasts are considered the main cell source for synthesis of the extracellular matrix (ECM) and as such a dysregulation in cFB function, activity, or viability can lead to disrupted ECM structure or fibrosis. Fibrosis can be initiated in response to different injuries and stimuli, and can be reparative (beneficial) or reactive (damaging). FBs need to be activated to myofibroblasts (MyoFBs) which have augmented capacity in synthesizing ECM proteins, causing fibrosis. In addition to the resident FBs in the myocardium, a number of other cells (pericytes, fibrocytes, mesenchymal, and hematopoietic cells) can transform into MyoFBs, further driving the fibrotic response. Multiple molecules including hormones, cytokines, and growth factors stimulate this process leading to generation of activated MyoFBs. Contribution of different cell types to cFBs and MyoFBs can result in an exponential increase in the number of MyoFBs and an accelerated pro-fibrotic response. Given the diversity of the cell sources, and the array of interconnected signalling pathways that lead to formation of MyoFBs and subsequently fibrosis, identifying a single target to limit the fibrotic response in the myocardium has been challenging. This review article will delineate the importance and relevance of fibroblast heterogeneity in mediating fibrosis in different models of heart failure and will highlight important signalling pathways implicated in myofibroblast activation.