title: Transcriptional control of cardiac fibroblast plasticity.
abstract: Cardiac fibroblasts help maintain the normal architecture of the healthy heart and are responsible for scar formation and the healing response to pathological insults. Various genetic, biomechanical, or humoral factors stimulate fibroblasts to become contractile smooth muscle-like cells called myofibroblasts that secrete large amounts of extracellular matrix. Unfortunately, unchecked myofibroblast activation in heart disease leads to pathological fibrosis, which is a major risk factor for the development of cardiac arrhythmias and heart failure. A better understanding of the molecular mechanisms that control fibroblast plasticity and myofibroblast activation is essential to develop novel strategies to specifically target pathological cardiac fibrosis without disrupting the adaptive healing response. This review highlights the major transcriptional mediators of fibroblast origin and function in development and disease. The contribution of the fetal epicardial gene program will be discussed in the context of fibroblast origin in development and following injury, primarily focusing on Tcf21 and C/EBP. We will also highlight the major transcriptional regulatory axes that control fibroblast plasticity in the adult heart, including transforming growth factor β (TGFβ)/Smad signaling, the Rho/myocardin-related transcription factor (MRTF)/serum response factor (SRF) axis, and Calcineurin/transient receptor potential channel (TRP)/nuclear factor of activated T-Cell (NFAT) signaling. Finally, we will discuss recent strategies to divert the fibroblast transcriptional program in an effort to promote cardiomyocyte regeneration. This article is a part of a Special Issue entitled "Fibrosis and Myocardial Remodeling".
authors.affiliation: Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY 14624, USA.
authors.forename: Janet K
authors.initials: JK
authors.lastname: Lighthouse
authors.affiliation: Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14624, USA; Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14624, USA; Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY 14624, USA. Electronic address: Eric_Small@URMC.Rochester.edu.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Small
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D005355:Fibrosis; D005786:Gene Expression Regulation; D006801:Humans; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D058628:Myofibroblasts / Q000166:cytology / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D026362:Serum Response Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D050052:TRPC Cation Channels / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C431575:MRTFA protein, human; D050778:NFATC Transcription Factors; C476858:SRF protein, human; D026362:Serum Response Factor; D050052:TRPC Cation Channels; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; C066737:RHOA protein, human; D019703:Calcineurin; D020742:rhoA GTP-Binding Protein
keywords: Cardiac fibroblast; Fibrosis; Heart; Myocardial infarction; Myofibroblast; Transcription