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Cardiac Fibroblasts, Fibrosis and Cardiovascular Disease

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cells of the Cardiovascular System".

Deadline for manuscript submissions: closed (20 June 2022) | Viewed by 34519

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Prof. Dr. Wayne Carver

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Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29209, USA
Interests: fibrosis; extracellular matrix; fibroblast activation; integrins; cardiovascular disease; alcohol abuse; decellularization; tissue engineering
Special Issues, Collections and Topics in MDPI journals

Dr. James A. Stewart

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Guest Editor

Department of Biomolecular Sciences, School of Pharmacy, The University of Mississippi, University, MS 38677, USA
Interests: cardiovascular disease; diabetes; AGE-RAGE signaling; fibroblasts; myofibroblasts; extracellular matrix remodeling
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The extracellular matrix plays a critical role in cardiac function as a three-dimensional scaffold that transmits mechanical forces throughout the myocardium and transduces essential signals to cardiac cells. The extracellular matrix is a highly dynamic network whose composition and organization change in order to meet the mechanical demands of tissues and organs. Fibrosis, or accumulation of an excessive collagenous extracellular matrix and matricellular components, is a common response to tissue injury in many organs. Fibrosis results in altered tissue biomechanical properties and deleteriously impacts tissue and organ function. In the heart, fibrosis is a predictor of adverse cardiovascular events, is an important driving force in diastolic dysfunction, and contributes to the progression of heart failure, one of the leading causes of death worldwide. Fibrosis is a highly complex process that includes a number of cell types including immune and inflammatory cells and diverse biochemical mediators. These mediators lead to the recruitment and activation of multiple cell types including quiescent fibroblasts, pericytes and mesenchymal stem cells into myofibroblasts that actively secrete extracellular matrix and chemokines/cytokines. Contrary to previous dogma, experimental models and clinical observations indicate that fibrosis may be reversible, leading to enhanced interest in identifying therapeutic targets that would lead to the regression of fibrosis. Development of effective therapies that specifically target fibrosis will require a greater understanding of the molecular and cellular mechanisms of this process.

This Special Issue aims to provide review and primary research articles focused on the cellular and molecular mechanisms of myocardial fibroblast activation and fibrosis and potential therapeutic approaches of these processes.

We look forward to your contributions to this exciting Special Edition of Cells.

Prof. Wayne Carver
Dr. James A. Stewart
Guest Editors

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Keywords

fibrosis
myofibroblast
heart
collagen
extracellular matrix

Published Papers (11 papers)

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Research

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20 pages, 3441 KiB

Open AccessArticle

Cardiac Tissue-like 3D Microenvironment Enhances Route towards Human Fibroblast Direct Reprogramming into Induced Cardiomyocytes by microRNAs

by Camilla Paoletti, Elena Marcello, Maria Luna Melis, Carla Divieto, Daria Nurzynska and Valeria Chiono

Cells 2022, 11(5), 800; https://doi.org/10.3390/cells11050800 - 25 Feb 2022

Cited by 11 | Viewed by 3653

Abstract

The restoration of cardiac functionality after myocardial infarction represents a major clinical challenge. Recently, we found that transient transfection with microRNA combination (miRcombo: miR-1, miR-133, miR-208 and 499) is able to trigger direct reprogramming of adult human cardiac fibroblasts (AHCFs) into induced cardiomyocytes (iCMs) in vitro. However, achieving efficient direct reprogramming still remains a challenge. The aim of this study was to investigate the influence of cardiac tissue-like biochemical and biophysical stimuli on direct reprogramming efficiency. Biomatrix (BM), a cardiac-like extracellular matrix (ECM), was produced by in vitro culture of AHCFs for 21 days, followed by decellularization. In a set of experiments, AHCFs were transfected with miRcombo and then cultured for 2 weeks on the surface of uncoated and BM-coated polystyrene (PS) dishes and fibrin hydrogels (2D hydrogel) or embedded into 3D fibrin hydrogels (3D hydrogel). Cell culturing on BM-coated PS dishes and in 3D hydrogels significantly improved direct reprogramming outcomes. Biochemical and biophysical cues were then combined in 3D fibrin hydrogels containing BM (3D BM hydrogel), resulting in a synergistic effect, triggering increased CM gene and cardiac troponin T expression in miRcombo-transfected AHCFs. Hence, biomimetic 3D culture environments may improve direct reprogramming of miRcombo-transfected AHCFs into iCMs, deserving further study. Full article

(This article belongs to the Special Issue Cardiac Fibroblasts, Fibrosis and Cardiovascular Disease)

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19 pages, 31931 KiB

Open AccessArticle

Quantitative Evaluation of Cardiac Cell Interactions and Responses to Cyclic Strain

by Richard Duc Hien Tran, Tessa Altair Morris, Daniela Gonzalez, Ali Hatem Salaheldin Hassan Ahmed Hetta and Anna Grosberg

Cells 2021, 10(11), 3199; https://doi.org/10.3390/cells10113199 - 17 Nov 2021

Cited by 3 | Viewed by 2913

Abstract

The heart has a dynamic mechanical environment contributed by its unique cellular composition and the resultant complex tissue structure. In pathological heart tissue, both the mechanics and cell composition can change and influence each other. As a result, the interplay between the cell phenotype and mechanical stimulation needs to be considered to understand the biophysical cell interactions and organization in healthy and diseased myocardium. In this work, we hypothesized that the overall tissue organization is controlled by varying densities of cardiomyocytes and fibroblasts in the heart. In order to test this hypothesis, we utilized a combination of mechanical strain, co-cultures of different cell types, and inhibitory drugs that block intercellular junction formation. To accomplish this, an image analysis pipeline was developed to automatically measure cell type-specific organization relative to the stretch direction. The results indicated that cardiac cell type-specific densities influence the overall organization of heart tissue such that it is possible to model healthy and fibrotic heart tissue in vitro. This study provides insight into how to mimic the dynamic mechanical environment of the heart in engineered tissue as well as providing valuable information about the process of cardiac remodeling and repair in diseased hearts. Full article

(This article belongs to the Special Issue Cardiac Fibroblasts, Fibrosis and Cardiovascular Disease)

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19 pages, 3383 KiB

Open AccessArticle

The Effects of Fibrotic Cell Type and Its Density on Atrial Fibrillation Dynamics: An In Silico Study

by Laura C. Palacio, Juan P. Ugarte, Javier Saiz and Catalina Tobón

Cells 2021, 10(10), 2769; https://doi.org/10.3390/cells10102769 - 15 Oct 2021

Cited by 5 | Viewed by 1762

Abstract

Remodeling in atrial fibrillation (AF) underlines the electrical and structural changes in the atria, where fibrosis is a hallmark of arrhythmogenic structural alterations. Fibrosis is an important feature of the AF substrate and can lead to abnormal conduction and, consequently, mechanical dysfunction. The fibrotic process comprises the presence of fibrotic cells, including fibroblasts, myofibroblasts and fibrocytes, which play an important role during fibrillatory dynamics. This work assesses the effect of the diffuse fibrosis density and the intermingled presence of the three types of fibrotic cells on the dynamics of persistent AF. For this purpose, the three fibrotic cells were electrically coupled to cardiomyocytes in a 3D realistic model of human atria. Low (6.25%) and high (25%) fibrosis densities were implemented in the left atrium according to a diffuse fibrosis representation. We analyze the action potential duration, conduction velocity and fibrillatory conduction patterns. Additionally, frequency analysis was performed in 50 virtual electrograms. The tested fibrosis configurations generated a significant conduction velocity reduction, where the larger effect was observed at high fibrosis density (up to 82% reduction in the fibrocytes configuration). Increasing the fibrosis density intensifies the vulnerability to multiple re-entries, zigzag propagation, and chaotic activity in the fibrillatory conduction. The most complex propagation patterns were observed at high fibrosis densities and the fibrocytes are the cells with the largest proarrhythmic effect. Left-to-right dominant frequency gradients can be observed for all fibrosis configurations, where the fibrocytes configuration at high density generates the most significant gradients (up to 4.5 Hz). These results suggest the important role of different fibrotic cell types and their density in diffuse fibrosis on the chaotic propagation patterns during persistent AF. Full article

(This article belongs to the Special Issue Cardiac Fibroblasts, Fibrosis and Cardiovascular Disease)

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13 pages, 2816 KiB

Open AccessArticle

Effects of Sex and 17 β-Estradiol on Cardiac Fibroblast Morphology and Signaling Activities In Vitro

by Kelsey Watts and William J. Richardson

Cells 2021, 10(10), 2564; https://doi.org/10.3390/cells10102564 - 28 Sep 2021

Cited by 4 | Viewed by 2221

Abstract

Several studies have demonstrated estrogen’s cardioprotective abilities in decreasing the fibrotic response of cardiac fibroblasts (CFs). However, the majority of these studies are not sex-specific, and those at the cellular level utilize tissue culture plastic, a substrate with a much higher stiffness than physiological conditions. Understanding the intrinsic differences between male and female CFs under more physiologically “healthy” conditions will help to elucidate the divergences in their complex signaling networks. We aimed to do this by conducting a sex-disaggregated analysis of changes in cellular morphology and relative levels of profibrotic signaling proteins in CFs cultured on 8 kPa stiffness plates with and without 17 β-estradiol (E2). Cyclic immunofluorescent analysis indicated that there was a negligible change in cellular morphology due to sex and E2 treatment and that the differences between male and female CFs occur at a biochemical rather than structural level. Several proteins corresponding to profibrotic activity had various sex-specific responses with and without E2 treatment. Single-cell correlation analysis exhibited varied protein–protein interaction across experimental conditions. These findings demonstrate the need for further research into the dimorphisms of male and female CFs to develop better tailored sex-informed prevention and treatment interventions of cardiac fibrosis. Full article

(This article belongs to the Special Issue Cardiac Fibroblasts, Fibrosis and Cardiovascular Disease)

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24 pages, 2511 KiB

Open AccessArticle

Rap1a Regulates Cardiac Fibroblast Contraction of 3D Diabetic Collagen Matrices by Increased Activation of the AGE/RAGE Cascade

by Stephanie D. Burr and James A. Stewart, Jr.

Cells 2021, 10(6), 1286; https://doi.org/10.3390/cells10061286 - 22 May 2021

Cited by 4 | Viewed by 2906

Abstract

Cardiovascular disease is a common diabetic complication that can arise when cardiac fibroblasts transition into myofibroblasts. Myofibroblast transition can be induced by advanced glycated end products (AGEs) present in the extracellular matrix (ECM) activating RAGE (receptor for advanced glycated end products) to elicit intracellular signaling. The levels of AGEs are higher under diabetic conditions due to the hyperglycemic conditions present in diabetics. AGE/RAGE signaling has been shown to alter protein expression and ROS production in cardiac fibroblasts, resulting in changes in cellular function, such as migration and contraction. Recently, a small GTPase, Rap1a, has been identified to overlap the AGE/RAGE signaling cascade and mediate changes in protein expression. While Rap1a has been shown to impact AGE/RAGE-induced protein expression, there are currently no data examining the impact Rap1a has on AGE/RAGE-induced cardiac fibroblast function. Therefore, we aimed to determine the impact of Rap1a on AGE/RAGE-mediated cardiac fibroblast contraction, as well as the influence isolated diabetic ECM has on facilitating these effects. In order to address this idea, genetically different cardiac fibroblasts were embedded in 3D collagen matrices consisting of collagen isolated from either non-diabetic of diabetic mice. Fibroblasts were treated with EPAC and/or exogenous AGEs, which was followed by assessment of matrix contraction, protein expression (α-SMA, SOD-1, and SOD-2), and hydrogen peroxide production. The results showed Rap1a overlaps the AGE/RAGE cascade to increase the myofibroblast population and generation of ROS production. The increase in myofibroblasts and oxidative stress appeared to contribute to increased matrix contraction, which was further exacerbated by diabetic conditions. Based off these results, we determined that Rap1a was essential in mediating the response of cardiac fibroblasts to AGEs within diabetic collagen. Full article

(This article belongs to the Special Issue Cardiac Fibroblasts, Fibrosis and Cardiovascular Disease)

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15 pages, 3414 KiB

Open AccessArticle

Genetic Deletion of Polo-Like Kinase 2 Induces a Pro-Fibrotic Pulmonary Phenotype

by Theresa A. Kant, Manja Newe, Luise Winter, Maximilian Hoffmann, Susanne Kämmerer, Erik Klapproth, Karolina Künzel, Mark P. Kühnel, Lavinia Neubert, Ali El-Armouche and Stephan R. Künzel

Cells 2021, 10(3), 617; https://doi.org/10.3390/cells10030617 - 11 Mar 2021

Cited by 7 | Viewed by 2294

Abstract

Pulmonary fibrosis is the chronic-progressive replacement of healthy lung tissue by extracellular matrix, leading to the destruction of the alveolar architecture and ultimately death. Due to limited pathophysiological knowledge, causal therapies are still missing and consequently the prognosis is poor. Thus, there is an urgent clinical need for models to derive effective therapies. Polo-like kinase 2 (PLK2) is an emerging regulator of fibroblast function and fibrosis. We found a significant downregulation of PLK2 in four different entities of human pulmonary fibrosis. Therefore, we characterized the pulmonary phenotype of PLK2 knockout (KO) mice. Isolated pulmonary PLK2 KO fibroblasts displayed a pronounced myofibroblast phenotype reflected by increased expression of αSMA, reduced proliferation rates and enhanced ERK1/2 and SMAD2/3 phosphorylation. In PLK2 KO, the expression of the fibrotic cytokines osteopontin and IL18 was elevated compared to controls. Histological analysis of PLK2 KO lungs revealed early stage remodeling in terms of alveolar wall thickening, increased alveolar collagen deposition and myofibroblast foci. Our results prompt further investigation of PLK2 function in pulmonary fibrosis and suggest that the PLK2 KO model displays a genetic predisposition towards pulmonary fibrosis, which could be leveraged in future research on this topic. Full article

(This article belongs to the Special Issue Cardiac Fibroblasts, Fibrosis and Cardiovascular Disease)

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11 pages, 2321 KiB

Open AccessFeature PaperArticle

Angiotensin II-Induced Cardiovascular Fibrosis Is Attenuated by NO-Sensitive Guanylyl Cyclase1

by Kathrin Broekmans, Jan Giesen, Lukas Menges, Doris Koesling and Michael Russwurm

Cells 2020, 9(11), 2436; https://doi.org/10.3390/cells9112436 - 08 Nov 2020

Cited by 7 | Viewed by 2184

Abstract

In the NO/cGMP signaling cascade, relevant in the cardiovascular system, two NO-sensitive guanylyl cyclase (NO-GC) isoforms are responsible for NO-dependent cGMP generation. Here, the impact of the major NO-GC isoform, NO-GC1, on fibrosis development in the cardiovascular system was studied in NO-GC1-deficient mice treated with AngiotensinII (AngII), known to induce vascular and cardiac remodeling. Morphometric analysis of NO-GC1 KO’s aortae demonstrated an enhanced increase of perivascular area after AngII treatment accompanied by a higher aortic collagen1 mRNA content. Increased perivascular fibrosis also occurred in cardiac vessels of AngII-treated NO-GC1 KO mice. In line, AngII-induced interstitial fibrosis was 32% more pronounced in NO-GC1 KO than in WT myocardia associated with a higher cardiac Col1 and other fibrotic marker protein content. In sum, increased perivascular and cardiac interstitial fibrosis together with the enhanced collagen1 mRNA content in AngII-treated NO-GC1-deficient mice represent an exciting manifestation of antifibrotic properties of cGMP formed by NO-GC1, a finding with great pharmaco-therapeutic implications. Full article

(This article belongs to the Special Issue Cardiac Fibroblasts, Fibrosis and Cardiovascular Disease)

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Review

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20 pages, 1888 KiB

Open AccessReview

Roles of Epigenetics in Cardiac Fibroblast Activation and Fibrosis

by Jingrong Shao, Jiao Liu and Shengkai Zuo

Cells 2022, 11(15), 2347; https://doi.org/10.3390/cells11152347 - 30 Jul 2022

Cited by 10 | Viewed by 3348

Abstract

Cardiac fibrosis is a common pathophysiologic process associated with numerous cardiovascular diseases, resulting in cardiac dysfunction. Cardiac fibroblasts (CFs) play an important role in the production of the extracellular matrix and are the essential cell type in a quiescent state in a healthy heart. In response to diverse pathologic stress and environmental stress, resident CFs convert to activated fibroblasts, referred to as myofibroblasts, which produce more extracellular matrix, contributing to cardiac fibrosis. Although multiple molecular mechanisms are implicated in CFs activation and cardiac fibrosis, there is increasing evidence that epigenetic regulation plays a key role in this process. Epigenetics is a rapidly growing field in biology, and provides a modulated link between pathological stimuli and gene expression profiles, ultimately leading to corresponding pathological changes. Epigenetic modifications are mainly composed of three main categories: DNA methylation, histone modifications, and non-coding RNAs. This review focuses on recent advances regarding epigenetic regulation in cardiac fibrosis and highlights the effects of epigenetic modifications on CFs activation. Finally, we provide some perspectives and prospects for the study of epigenetic modifications and cardiac fibrosis. Full article

(This article belongs to the Special Issue Cardiac Fibroblasts, Fibrosis and Cardiovascular Disease)

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12 pages, 1008 KiB

Open AccessReview

CVD and COVID-19: Emerging Roles of Cardiac Fibroblasts and Myofibroblasts

by Laxmansa C. Katwa, Chelsea Mendoza and Madison Clements

Cells 2022, 11(8), 1316; https://doi.org/10.3390/cells11081316 - 13 Apr 2022

Cited by 12 | Viewed by 3556

Abstract

Cardiovascular disease (CVD) is the leading cause of death worldwide. Current data suggest that patients with cardiovascular diseases experience more serious complications with coronavirus disease-19 (COVID-19) than those without CVD. In addition, severe COVID-19 appears to cause acute cardiac injury, as well as long-term adverse remodeling of heart tissue. Cardiac fibroblasts and myofibroblasts, being crucial in response to injury, may play a pivotal role in both contributing to and healing COVID-19-induced cardiac injury. The role of cardiac myofibroblasts in cardiac fibrosis has been well-established in the literature for decades. However, with the emergence of the novel coronavirus SARS-CoV-2, new cardiac complications are arising. Bursts of inflammatory cytokines and upregulation of TGF-β1 and angiotensin (AngII) are common in severe COVID-19 patients. Cytokines, TGF-β1, and Ang II can induce cardiac fibroblast differentiation, potentially leading to fibrosis. This review details the key information concerning the role of cardiac myofibroblasts in CVD and COVID-19 complications. Additionally, new factors including controlling ACE2 expression and microRNA regulation are explored as promising treatments for both COVID-19 and CVD. Further understanding of this topic may provide insight into the long-term cardiac manifestations of the COVID-19 pandemic and ways to mitigate its negative effects. Full article

(This article belongs to the Special Issue Cardiac Fibroblasts, Fibrosis and Cardiovascular Disease)

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22 pages, 1440 KiB

Open AccessReview

Roles of Exosomes in Cardiac Fibroblast Activation and Fibrosis

by Julia Hohn, Wenbin Tan, Amanda Carver, Hayden Barrett and Wayne Carver

Cells 2021, 10(11), 2933; https://doi.org/10.3390/cells10112933 - 28 Oct 2021

Cited by 8 | Viewed by 3391

Abstract

Alterations in the accumulation and composition of the extracellular matrix are part of the normal tissue repair process. During fibrosis, this process becomes dysregulated and excessive extracellular matrix alters the biomechanical properties and function of tissues involved. Historically fibrosis was thought to be progressive and irreversible; however, studies suggest that fibrosis is a dynamic process whose progression can be stopped and even reversed. This realization has led to an enhanced pursuit of therapeutic agents targeting fibrosis and extracellular matrix-producing cells. In many organs, fibroblasts are the primary cells that produce the extracellular matrix. In response to diverse mechanical and biochemical stimuli, these cells are activated or transdifferentiate into specialized cells termed myofibroblasts that have an enhanced capacity to produce extracellular matrix. It is clear that interactions between diverse cells of the heart are able to modulate fibroblast activation and fibrosis. Exosomes are a form of extracellular vesicle that play an important role in intercellular communication via the cargo that they deliver to target cells. While relatively recently discovered, exosomes have been demonstrated to play important positive and negative roles in the regulation of fibroblast activation and tissue fibrosis. These roles as well as efforts to engineer exosomes as therapeutic tools will be discussed. Full article

(This article belongs to the Special Issue Cardiac Fibroblasts, Fibrosis and Cardiovascular Disease)

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21 pages, 2955 KiB

Open AccessFeature PaperReview

Are Interactions between Epicardial Adipose Tissue, Cardiac Fibroblasts and Cardiac Myocytes Instrumental in Atrial Fibrosis and Atrial Fibrillation?

by Anirudh Krishnan, Emily Chilton, Jaishankar Raman, Pankaj Saxena, Craig McFarlane, Alexandra F. Trollope, Robert Kinobe and Lisa Chilton

Cells 2021, 10(9), 2501; https://doi.org/10.3390/cells10092501 - 21 Sep 2021

Cited by 27 | Viewed by 4514

Abstract

Atrial fibrillation is very common among the elderly and/or obese. While myocardial fibrosis is associated with atrial fibrillation, the exact mechanisms within atrial myocytes and surrounding non-myocytes are not fully understood. This review considers the potential roles of myocardial fibroblasts and myofibroblasts in fibrosis and modulating myocyte electrophysiology through electrotonic interactions. Coupling with (myo)fibroblasts in vitro and in silico prolonged myocyte action potential duration and caused resting depolarization; an optogenetic study has verified in vivo that fibroblasts depolarized when coupled myocytes produced action potentials. This review also introduces another non-myocyte which may modulate both myocardial (myo)fibroblasts and myocytes: epicardial adipose tissue. Epicardial adipocytes are in intimate contact with myocytes and (myo)fibroblasts and may infiltrate the myocardium. Adipocytes secrete numerous adipokines which modulate (myo)fibroblast and myocyte physiology. These adipokines are protective in healthy hearts, preventing inflammation and fibrosis. However, adipokines secreted from adipocytes may switch to pro-inflammatory and pro-fibrotic, associated with reactive oxygen species generation. Pro-fibrotic adipokines stimulate myofibroblast differentiation, causing pronounced fibrosis in the epicardial adipose tissue and the myocardium. Adipose tissue also influences myocyte electrophysiology, via the adipokines and/or through electrotonic interactions. Deeper understanding of the interactions between myocytes and non-myocytes is important to understand and manage atrial fibrillation. Full article

(This article belongs to the Special Issue Cardiac Fibroblasts, Fibrosis and Cardiovascular Disease)

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