Myofibroblasts: trust your heart and let fate decide

Abstract

Cardiac fibrosis is a substantial problem in managing multiple forms of heart disease. Fibrosis results from an unrestrained tissue repair process orchestrated predominantly by the myofibroblast. These are highly specialized cells characterized by their ability to secrete extracellular matrix (ECM) components and remodel tissue due to their contractile properties. This contractile activity of the myofibroblast is ascribed, in part, to the expression of smooth muscle α-actin (αSMA) and other tension-associated structural genes. Myofibroblasts are a newly generated cell type derived largely from residing mesenchymal cells in response to both mechanical and neurohumoral stimuli. Several cytokines, chemokines, and growth factors are induced in the injured heart, and in conjunction with elevated wall tension, specific signaling pathways and downstream effectors are mobilized to initiate myofibroblast differentiation. Here we will review the cell fates that contribute to the myofibroblast as well as nodal molecular signaling effectors that promote their differentiation and activity. We will discuss canonical versus non-canonical transforming growth factor-β (TGFβ), angiotensin II (AngII), endothelin-1 (ET-1), serum response factor (SRF), transient receptor potential (TRP) channels, mitogen-activated protein kinases (MAPKs) and mechanical signaling pathways that are required for myofibroblast transformation and fibrotic disease. This article is part of a Special Issue entitled "Myocyte-Fibroblast Signalling in Myocardium ".

Keywords: Angiotensin II; Extracellular matrix; Fibrosis; Serum response factor; TGFβ; TRP channel.

Fig. 1. Myofibroblast precursor cell fates

Myofibroblasts can originate from several cellular sources during tissue injury. Cells resident to the tissue of interest including fibroblasts, smooth muscle cells (SMCs) and vascular pericytes can all differentiate into a myofibroblast, which can then facilitate acute injury repair processes and tissue remodeling. The hypothesized cellular sources for myofibroblasts during chronic injury include endothelial and epithelial cells that can undergo mesenchymal transition (EMT) and circulating bone marrow derived cells including fibrocytes and myeloid cells, although resident fibroblast sources that generate myofibroblasts could also participate in long-term chronic disease states.

Fig. 2. Integrated signaling pathways in myofibroblast transformation

Canonical (purples) and non-canonical (blues) TGFβ signaling are illustrated as converging on SMAD2/3 or SRF mediated transcription of myofibroblast genes, respectively. Neurohumoral signaling via AngII or ET-1 binding to its membrane localized G-protein-coupled receptor (GPCR) is depicted initiating myofibroblast gene transcription through p38/SRF (dark line) but also possibly leading to RhoA signaling (dashed line), similar to a presumed linkage between TGFβRI/II and RhoA signaling. The RhoA-MRTF-SRF signaling axis (red-shaded) is depicted as regulating smooth muscle actin (αSMA) dynamics and MRTF translocation to the nucleus to serve as a synergistic cofactor for SRF transcriptional activity of myofibroblast genes. Non-canonical TGFβ-p38-SRF activates TRPC6-Ca²⁺-calcineurin-NFAT signaling is also mediating myofibroblast gene transcription. Mechanical tension activates myofibroblast differentiation through stretch-sensitive ion channels, activation of latent TGFβ, RhoA-MRTF and p38 through signals from the cytoskeleton. Together these signaling events amplify and reinforce the transcriptional pathways responsible for myofibroblast differentiation.