The Living Scar – Cardiac Fibroblasts and the Injured Heart

Abstract

Cardiac scars, often perceived as “dead” tissue, are very much alive, with heterocellular activity ensuring the maintenance of structural and mechanical integrity following heart injury. To form a scar, non-myocytes such as fibroblasts, proliferate and are recruited from intra- and extra-cardiac sources. Fibroblasts perform important autocrine and paracrine signalling functions. They also establish mechanical and, as is increasingly evident, electrical junctions with other cells. While fibroblasts were previously thought to act simply as electrical insulators, they may be electrically connected among themselves and, under certain circumstances, to other cells, including cardiomyocytes. A better understanding of these interactions will help target scar structure and function and facilitate the development of novel therapies aimed at modifying scar properties for patient benefit. This review explores available insight and recent concepts on fibroblast integration in the heart, and highlights potential avenues for harnessing their roles to optimise scar function following heart injury such as infarction, and therapeutic interventions such as ablation.

Piezo channels and GsMTx4: Two milestones in our understanding of excitatory mechanosensitive channels and their role in pathology

“…These cardioprotective effects may be due to improved blood flow to ischemic tissue during hypoxia since GsMTx4 causes vascular smooth muscle relaxation by both decreasing mechanically activated excitatory cation currents [110, 111] and down regulation of endothelin-1 stimulated increase in arterial resistance [112, 113]. It may also affect fibroblast conductive properties which are known to play a role in generation of arrhythmias following ischemia [114, 115]. In this regard GsMTx4’s potentiation of K2P and SAKCa channels may also be important aspects of its antiarrhythmic effect.…”

Fibroblast–myocyte coupling in the heart: Potential relevance for therapeutic interventions

“…Additionally cardiac fibroblasts can originate from the cardiac endothelium, undergoing endothelial to mesenchymal transformation [26–28]. Although perhaps not frequent in normal homeostasis, other contributor pools to the cardiac fibroblast population include bone marrow-derived cells [8,9,10], hematopoietic cells [32], and mesangioblasts [33] (for review, see [34]).…”

“…These thin (20–50 nm wide) membranous tubes can stretch between dendritic corneal cells as far apart as 300 μm in vivo [58], and they can propagate AP from cell to cell [59]. While evidence of myocyte-fibroblast coupling via nanotubes has been shown in vivo and in vitro [57], the electrophysiological function of nanotubes in the myocardium in health or disease has yet to be ascertained [34]. …”

Turning regenerative technologies into treatment to repair myocardial injuries

“…Fibroblasts, previously thought to act as simple electrical insulators, can be electrically interconnected among themselves and to other cells, including cardiomyocytes. In addition, fibroblasts are noted to perform important autocrine and paracrine signalling functions due to their abundance, strategic location, phenotypic plasticity, ability to communicate with different cell types and active participation in cardiac mechanical and electrical activity . Thus, cardiac fibroblasts may be key therapeutic targets in cardiac remodelling and repair.…”