Complex Relationship Between Cardiac Fibroblasts and Cardiomyocytes in Health and Disease

Abstract

Cardiac fibroblasts are the primary cell type responsible for deposition of extracellular matrix in the heart, providing support to the contracting myocardium and contributing to a myriad of physiological signaling processes. Despite the importance of fibrosis in processes of wound healing, excessive fibroblast proliferation and activation can lead to pathological remodeling, driving heart failure and the onset of arrhythmias. Our understanding of the mechanisms driving the cardiac fibroblast activation and proliferation is expanding, and evidence for their direct and indirect effects on cardiac myocyte function is accumulating. In this review, we focus on the importance of the fibroblast-to-myofibroblast transition and the cross talk of cardiac fibroblasts with cardiac myocytes. We also consider the current use of models used to explore these questions.

Keywords: arrhythmias; cardiac fibroblasts; cardiomyocytes; fibrosis; heart failure; myofibroblast.

Figure 1. Resident cardiac fibroblasts (cFbs) derive from endothelial‐to‐mesenchymal or epithelial‐to‐mesenchymal transition.

Injury to the myocardium initiates signaling pathways that trigger the activation of cFbs to myofibroblasts (MyoFbs). Loss of structural integrity via cardiomyocyte (CM) death also creates mechanical stress that mediates cFb to MyoFb activation. Consequences of MyoFb activation vary between repair and disease processes. There are multiple mechanisms for activation, including mechanical stimuli and paracrine factors, such as transforming growth factor‐β (TGF‐β) and angiotensin II (Ang II), from a variety of different sources, such as CMs and the cFbs themselves. ²⁸ , ⁴³

Figure 2. Figure depicting cardiomyocyte (CM)–myofibroblast (MyoFb) communcations.

Gap junctions are present at distal junctions between CMs as well as elsewhere between CMs and MyoFbs. Gap junctions and membrane nanotubes allow exchange of molecules between the cytoplasms of cells. Paracrine factors secreted by cells bind receptors on neighbouring membranes, initiating signaling pathways. cFb indicates cardiac fibroblast.

Figure 3. Schematic of transforming growth factor‐β (TGF‐β) activation via small mothers against decapentaplegic (Smad) signaling.

TGF‐β binds its receptor, initiating phosphorylation (p) of Smad2/3. This complex then binds Smad4 and translocates to the nucleus to induce transcription of target genes involved in proliferation, collagen production, and activation of cardiac fibroblasts to myofibroblasts (MyoFbs). ⁴² , ⁷⁵

Figure 4. Schematic of transforming growth factor‐β (TGF‐β) activation via noncanonical (small mothers against decapentaplegic–independent) signaling.

TGF‐β binds its receptor, initiating activation of Ras or TAK1 and further downsteam activation of extracellular signal‐regulated kinase (ERK), JNK, or p38. This leads to promotion of transcription factors (TFs) and the transcription of target genes involved in myofibroblast (MyoFb) activation, fibrosis, and cardiomyocyte apoptosis. ⁷⁹ MAPK indicates mitogen‐activated protein kinase.