The Soft- and Hard-Heartedness of Cardiac Fibroblasts: Mechanotransduction Signaling Pathways in Fibrosis of the Heart

Herum, Kate Louise Møller; Lunde, Ida G.; McCulloch, Andrew D.; Christensen, Geir

doi:10.3390/jcm6050053

Cited by 140 publications

(131 citation statements)

References 280 publications

(394 reference statements)

Supporting

Mentioning

123

Contrasting

Order By: Relevance

“…Fibroblasts are highly responsive to post-infarct biochemical cues consisting of pro-inflammatory cytokines, growth factors, and hormonal agents that stimulate fibroblasts to degrade or deposit ECM. A growing body of research has also shown that fibroblast functionality is dependent on local mechanical cues; MI-induced loss of cardiomyocytes results in increased circumferential stretch at the infarct [5,6], which stimulates fibroblast activation through several mechano-sensing mechanisms [7]. While biochemical and mechanical signaling pathways have been studied individually in cardiac fibroblasts, few studies have examined the interplay between biochemical and mechanical signaling.…”

Section: Introductionmentioning

confidence: 99%

Mechano-Chemo Signaling Interactions Modulate Matrix Production by Cardiac Fibroblasts

Rogers

Holmes

Saucerman

et al. 2020

Preprint

View full text Add to dashboard Cite

Extracellular matrix remodeling after myocardial infarction occurs in a dynamic environment in which local mechanical stresses and biochemical signaling species stimulate the accumulation of collagen-rich scar tissue. It is well-known that cardiac fibroblasts regulate postinfarction matrix turnover by secreting matrix proteins, proteases, and protease inhibitors in response to both biochemical stimuli and mechanical stretch, but how these stimuli act together to dictate cellular responses is still unclear. We developed a screen of cardiac fibroblast-secreted proteins in response to combinations of biochemical agonists and cyclic uniaxial stretch in order to elucidate the relationships between stretch, biochemical signaling, and cardiac matrix turnover.We found that stretch significantly synergized with biochemical agonists to inhibit the secretion of matrix metalloproteinases, with stretch either amplifying protease suppression by individual agonists or antagonizing agonist-driven upregulation of protease expression. Stretch also modulated fibroblast sensitivity towards biochemical agonists by either sensitizing cells towards agonists that suppress protease secretion or de-sensitizing cells towards agonists that upregulate protease secretion. These findings suggest that the mechanical environment can significantly alter fibrosis-related signaling in cardiac fibroblasts, suggesting caution when extrapolating in vitro data to predict effects of fibrosis-related cytokines in situations like myocardial infarction where mechanical stretch occurs.

show abstract

Section: Introductionmentioning

confidence: 99%

Mechano-Chemo Signaling Interactions Modulate Matrix Production by Cardiac Fibroblasts

Rogers

Holmes

Saucerman

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Our observation that Piezo1 opposes myofibroblast differentiation is intriguing as mechanical stimulation is known to be an important driver of myofibroblast differentiation which, along with TGF-β, induces changes in gene expression including upregulation of α-SMA. Activation of integrins, TRP channels and cytoskeletal complexes have been shown to translate mechanical signals into changes in cardiac fibroblast gene expression including those involved in myofibroblast differentiation [4,5]. However, our data suggest that Piezo1 acts to oppose these signals.…”

Section: Discussionmentioning

confidence: 59%

“…Much remains unknown regarding how mechanical forces are translated into transcriptional responses important for determination of the fibroblast phenotype and how this can lead to cardiac remodeling [4,5]. Stretch-activated ion channels have been identified as candidates for cardiac mechanotransducers [6].…”

Section: Introductionmentioning

confidence: 99%

Stimulation of cardiac fibroblast Piezo1 channels opposes myofibroblast differentiation and induces IL-6 secretion via Ca²⁺-mediated p38 MAP kinase activation

Stylianidis

et al. 2019

Preprint

View full text Add to dashboard Cite

Piezo1 is a mechanosensitive cation channel with widespread physiological importance; however its role in the heart is poorly understood. Cardiac fibroblasts are responsible for preserving the structural integrity of the myocardium and play a key role in regulating its repair and remodeling following stress or injury. We investigated expression and function of Piezo1 in cultured human and mouse cardiac fibroblasts. RT-PCR studies confirmed expression of Piezo1 mRNA in cardiac fibroblasts at similar levels to endothelial cells. Fura-2 intracellular Ca 2+ measurements validated Piezo1 as a functional ion channel that was activated by the Piezo1 agonist, Yoda1. Yoda1induced Ca 2+ entry was inhibited by Piezo1 blockers (gadolinium, ruthenium red) and the Ca 2+ response was reduced proportionally by Piezo1 siRNA knockdown or in cells from Piezo1 +/mice.Investigation of Yoda1 effects on selected remodeling genes indicated that Piezo1 activation opposed cardiac fibroblast differentiation; data confirmed by functional collagen gel contraction assays. Piezo1 activation using Yoda1 or mechanical stretch also increased the expression of interleukin-6 (IL-6), a mechanosensitive pro-hypertrophic and pro-fibrotic cytokine, in a Piezo1dependent manner. Multiplex kinase activity profiling combined with kinase inhibitor studies and phospho-specific western blotting, established that Piezo1 activation stimulated IL-6 secretion via a pathway involving p38 MAP kinase, downstream of Ca 2+ entry. In summary, this study reveals that cardiac fibroblasts express functional Piezo1 channels coupled to reduced myofibroblast activation and increased secretion of paracrine signaling molecules that can modulate cardiac remodeling.

show abstract

“…Cardiac fibroblast activation is affected by mechanical cues through direct translation of cytoskeleton tensioning into intracellular activation cascades or by controlling the release of paracrine signals [42]. For example, the persistent elevated stretch of mice cardiac fibroblasts, mimicking the mechanics of the infarct region, stimulates sustained production of ECM, causing myocardial stiffening [43] (Figure 3). Moreover, matrix hardening associated with infarct scar maturation induces cell spreading, formation of smooth muscle α-actin stress fiber and expression of collagens I/III [42,43].…”

Section: Role Of Mechanical Factors In Myofibroblast Activation and Cmentioning

confidence: 99%

“…For example, the persistent elevated stretch of mice cardiac fibroblasts, mimicking the mechanics of the infarct region, stimulates sustained production of ECM, causing myocardial stiffening [43] (Figure 3). Moreover, matrix hardening associated with infarct scar maturation induces cell spreading, formation of smooth muscle α-actin stress fiber and expression of collagens I/III [42,43]. The complex YAP/TAZ, involved in cell mechanosensing [44], exerts a crucial role in adult cardiac fibroblasts migration, proliferation and differentiation [45].…”

Section: Role Of Mechanical Factors In Myofibroblast Activation and Cmentioning

confidence: 99%

Mechanotransduction in the Cardiovascular System: From Developmental Origins to Homeostasis and Pathology

Garoffolo

Pesce

2019

Cells

View full text Add to dashboard Cite

With the term 'mechanotransduction', it is intended the ability of cells to sense and respond to mechanical forces by activating intracellular signal transduction pathways and the relative phenotypic adaptation. While a known role of mechanical stimuli has been acknowledged for developmental biology processes and morphogenesis in various organs, the response of cells to mechanical cues is now also emerging as a major pathophysiology determinant. Cells of the cardiovascular system are typically exposed to a variety of mechanical stimuli ranging from compression to strain and flow (shear) stress. In addition, these cells can also translate subtle changes in biophysical characteristics of the surrounding matrix, such as the stiffness, into intracellular activation cascades with consequent evolution toward pro-inflammatory/pro-fibrotic phenotypes. Since cellular mechanotransduction has a potential readout on long-lasting modifications of the chromatin, exposure of the cells to mechanically altered environments may have similar persisting consequences to those of metabolic dysfunctions or chronic inflammation. In the present review, we highlight the roles of mechanical forces on the control of cardiovascular formation during embryogenesis, and in the development and pathogenesis of the cardiovascular system.In the present contribution, we will focus on the role of mechanical forces in controlling the morphogenesis of the cardiovascular system and on their new emerging role as a pathology determinant. We will also describe how traction forces exerted locally by single cells or forces (e.g., laminar/perturbed shear stress, constant/oscillatory pressure) propagated passively in the tissues are converted into signals regulating intracellular biochemistry and gene expression underlying pathology progression. Definition of Cell Mechanotransduction: Outside-In and Inside-Out Communication in the Complex 3D Environment Similar to classical ligand/receptor interactions, mechanotransduction requires binding of cell surface receptors to their ligands immobilized into the extracellular matrix (ECM), or expressed at the surface of adjacent cells. Differences in the mechanical features of the ECM, or in the geometrical arrangement of receptor binding motifs, can have a direct readout on cell proliferation, differentiation and migratory responses. Mechanical cues are converted into biochemical signals by activation of intracellular cascades transmitted via the cytoskeleton and their components, for example the acto-myosin 'stress' fibers [4], the microtubules [5], the scaffolding proteins [6], and various kinases and phosphatases [7] (Figure 1). Cells 2019, 8, x 2 of 18asymmetric cellular divisions and establishment of initial embryonic polarity. Thereafter, the mechanotransduction process continues in adult life, contributing to tissue growth, homeostasis and, finally, disease programming. In the present contribution, we will focus on the role of mechanical forces in controlling the morphogenesis of the cardiovascular system and on...

show abstract

The Soft- and Hard-Heartedness of Cardiac Fibroblasts: Mechanotransduction Signaling Pathways in Fibrosis of the Heart

Cited by 140 publications

References 280 publications

Mechano-Chemo Signaling Interactions Modulate Matrix Production by Cardiac Fibroblasts

Mechano-Chemo Signaling Interactions Modulate Matrix Production by Cardiac Fibroblasts

Stimulation of cardiac fibroblast Piezo1 channels opposes myofibroblast differentiation and induces IL-6 secretion via Ca²⁺-mediated p38 MAP kinase activation

Mechanotransduction in the Cardiovascular System: From Developmental Origins to Homeostasis and Pathology

Contact Info

Product

Resources

About

The Soft- and Hard-Heartedness of Cardiac Fibroblasts: Mechanotransduction Signaling Pathways in Fibrosis of the Heart

Cited by 140 publications

References 280 publications

Mechano-Chemo Signaling Interactions Modulate Matrix Production by Cardiac Fibroblasts

Mechano-Chemo Signaling Interactions Modulate Matrix Production by Cardiac Fibroblasts

Stimulation of cardiac fibroblast Piezo1 channels opposes myofibroblast differentiation and induces IL-6 secretion via Ca2+-mediated p38 MAP kinase activation

Mechanotransduction in the Cardiovascular System: From Developmental Origins to Homeostasis and Pathology

Contact Info

Product

Resources

About

Stimulation of cardiac fibroblast Piezo1 channels opposes myofibroblast differentiation and induces IL-6 secretion via Ca²⁺-mediated p38 MAP kinase activation