Intracellular Signaling of Cardiac Fibroblasts

Abstract

Long regarded as a mere accessory cell for the cardiomyocyte, the cardiac fibroblast is now recognized as a critical determinant of cardiac function in health and disease. A recent renaissance in fibroblast-centered research has fostered a better understanding than ever before of the biology of fibroblasts and their contractile counterparts, myofibroblasts. While advanced methodological approaches, including transgenics, lineage fate mapping, and improved cell marker identification have helped to facilitate this new work, the primary driver is arguably the contribution of myofibroblasts to cardiac pathophysiology including fibrosis and arrhythmogenesis. Fibrosis is a natural sequel to numerous common cardiac pathologies including myocardial infarction and hypertension, and typically exacerbates cardiovascular disease and progression to heart failure, yet no therapies currently exist to specifically target fibrosis. The regulatory processes and intracellular signaling pathways governing fibroblast and myofibroblast behavior thus represent important points of inquiry for the development of antifibrotic treatments. While steady progress is being made in uncovering the signaling pathways specific for cardiac fibroblast function (including proliferation, phenotype conversion, and matrix synthesis), much of what is currently known of fibroblast signaling mechanisms is derived from noncardiac fibroblast populations. Given the heterogeneity of fibroblasts across tissues, this dearth of information further underscores the need for progress in cardiac fibroblast biological research.

Role of scleraxis in mechanical stretch-mediated regulation of cardiac myofibroblast phenotype

“…Although cardiac myofibroblasts are critical for deposition of a collagen-rich matrix following myocardial infarction, their persistence in the noninfarcted and distal regions of the myocardium is the basis for cardiac fibrosis (38). Although many factors have been shown to be involved in the conversion of cardiac fibroblasts to myofibroblasts, many of these (such as TGF-␤) are pleiotropic molecules that represent poor choices for therapeutic targets.…”

“…Cardiac fibrosis entails a poor prognosis, negatively impacting both systolic and diastolic function and eventually leading to heart failure and death (43). There currently exists no treatment for the arrest or reversal of cardiac fibrosis (38). However, alteration of the myofibroblast phenotype may provide a novel means for the treatment and even reversal of fibrotic lesions in various tissue types (20,21,23,26,34,37,49).…”

Novel therapeutic strategies targeting fibroblasts and fibrosis in heart disease

“…These cells also have important roles in the active secretion and turnover of collagen and other ECM molecules 10 and are responsive to hypoxia, cytokines and signalling molecules associated with the inflammatory milieu, such as TGFβ, tumor necrosis factor α, interleukin-6 (IL-6), and IL-2. 1, 3, 5, 6, 92 Activated fibroblasts are a common component of granulation tissue throughout the body, typically peaking in density at 4–6 days post-injury. An interesting difference between wound healing in skin vs. heart is that myofibroblasts appear to persist (for up to 17 years!)…”

Myofibroblast secretome and its auto-/paracrine signaling

“…Interleukins 1, 6, and 13, and noncoding RNA molecules are involved in regulating myofibroblast collagen synthesis [51]. Intracellular signaling pathways regulating the myofibroblast secretome and collagen turnover are under investigation [52]. TGF-β 1 , for example, regulates myofibroblast expression of scleraxis, a profibrotic transcription factor which stimulates collagen synthesis via a Smad-independent pathway [53].…”