Fibroblast Diversity and Epigenetic Regulation in Cardiac Fibrosis

Abstract

Cardiac fibrosis, a process characterized by excessive extracellular matrix (ECM) deposition, is a common pathological consequence of many cardiovascular diseases (CVDs) normally resulting in organ failure and death. Cardiac fibroblasts (CFs) play an essential role in deleterious cardiac remodeling and dysfunction. In response to injury, quiescent CFs become activated and adopt a collagen-secreting phenotype highly contributing to cardiac fibrosis. In recent years, studies have been focused on the exploration of molecular and cellular mechanisms implicated in the activation process of CFs, which allow the development of novel therapeutic approaches for the treatment of cardiac fibrosis. Transcriptomic analyses using single-cell RNA sequencing (RNA-seq) have helped to elucidate the high cellular diversity and complex intercellular communication networks that CFs establish in the mammalian heart. Furthermore, a significant body of work supports the critical role of epigenetic regulation on the expression of genes involved in the pathogenesis of cardiac fibrosis. The study of epigenetic mechanisms, including DNA methylation, histone modification, and chromatin remodeling, has provided more insights into CF activation and fibrotic processes. Targeting epigenetic regulators, especially DNA methyltransferases (DNMT), histone acetylases (HAT), or histone deacetylases (HDAC), has emerged as a promising approach for the development of novel anti-fibrotic therapies. This review focuses on recent transcriptomic advances regarding CF diversity and molecular and epigenetic mechanisms that modulate the activation process of CFs and their possible clinical applications for the treatment of cardiac fibrosis.

Keywords: cardiac fibroblast; epigenetics; fibrosis; therapeutic approach; transcriptomics.

Figure 1

Epigenetic regulation in cardiac fibrosis. In response to pathological stresses, the epigenetic machinery is activated to promote cardiac fibroblast (CF) activation, leading to cardiac fibrosis. The complex interaction between DNA methyltransferases (DNMT), tet methylcytosine dioxygenases (TET) (DNA methylation), lysine methyltransferases (KMT), lysine demethylases (KDM), histone deacetylases (HDAC), histone acetyltransferases (HAT), bromodomain and extra-terminal motif proteins (BET) (Histone modifications), and ISWI, CHD, SWI/SNF, and INO80 complexes (Chromatin remodeling) govern the methylation (Me) of DNA and histones, the acetylation (Ac) of histones, and changes in nucleosomes, consequently impacting the progression of cardiac fibrosis. The therapeutic administration of epigenetic drugs targeting these epigenetic regulators may revert the pathological consequences of specific epigenetic mechanisms in the development of fibrotic disease. This figure was created with BioRender.com.