Human Atrial Fibroblast Adaptation to Heterogeneities in Substrate Stiffness

Emig, Ramona; Zgierski-Johnston, Callum M.; Beyersdorf, Friedhelm; Rylski, Bartosz; Ravens, Ursula; Weber, Wilfried; Kohl, Peter; Hörner, Maximilian; Peyronnet, Rémi

doi:10.3389/fphys.2019.01526

Cited by 16 publications

(21 citation statements)

References 34 publications

(40 reference statements)

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“…HAF respond to higher stiffness of their growth matrix by becoming stiffer themselves, which is in line with the response of primary human atrial fibroblasts [ 44 ] and corresponds to one of the canonical cell adaptations to matrix stiffness [ 62 ]. We show that Piezo1 contributes critically to this ability, as HAF stiffness adaptation to differences in matrix mechanical properties was abolished with Piezo1 knock-down.…”

Section: Discussionmentioning

confidence: 59%

“…In short, the cyanobacterial photoreceptor-1 was recombinantly expressed, purified and covalently coupled to 8-arm polyethylene glycol. For casting, 30 µL of CyPhyGel solution was spread on square (22 by 22 mm) coverslips, resulting in CyPhyGels with ≈100 µm thickness, tunable by illumination with light of different wavelengths to a stiffness between 2.7 and 4.6 kPa [ 42 , 44 ].…”

Section: Methodsmentioning

confidence: 99%

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Piezo1 Channels Contribute to the Regulation of Human Atrial Fibroblast Mechanical Properties and Matrix Stiffness Sensing

Emig

Knodt

Krussig

et al. 2021

Cells

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The mechanical environment of cardiac cells changes continuously and undergoes major alterations during diseases. Most cardiac diseases, including atrial fibrillation, are accompanied by fibrosis which can impair both electrical and mechanical function of the heart. A key characteristic of fibrotic tissue is excessive accumulation of extracellular matrix, leading to increased tissue stiffness. Cells are known to respond to changes in their mechanical environment, but the molecular mechanisms underlying this ability are incompletely understood. We used cell culture systems and hydrogels with tunable stiffness, combined with advanced biophysical and imaging techniques, to elucidate the roles of the stretch-activated channel Piezo1 in human atrial fibroblast mechano-sensing. Changing the expression level of Piezo1 revealed that this mechano-sensor contributes to the organization of the cytoskeleton, affecting mechanical properties of human embryonic kidney cells and human atrial fibroblasts. Our results suggest that this response is independent of Piezo1-mediated ion conduction at the plasma membrane, and mediated in part by components of the integrin pathway. Further, we show that Piezo1 is instrumental for fibroblast adaptation to changes in matrix stiffness, and that Piezo1-induced cell stiffening is transmitted in a paracrine manner to other cells by a signaling mechanism requiring interleukin-6. Piezo1 may be a new candidate for targeted interference with cardiac fibroblast function.

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Section: Discussionmentioning

confidence: 59%

Section: Methodsmentioning

confidence: 99%

Piezo1 Channels Contribute to the Regulation of Human Atrial Fibroblast Mechanical Properties and Matrix Stiffness Sensing

Emig

Knodt

Krussig

et al. 2021

Cells

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“…The mechanical properties of cells in response to the indicated treatments were assessed using the Chiaro nanoindenter system (Optics11, Amsterdam, the Netherlands) as described previously (Emig et al 2019 ). Briefly, a spherical tip with a 3-μm radius, attached to a calibrated cantilever with a spring constant of 0.03 N/m, was used to indent the sample while the bending of the cantilever was tracked by interferometry (Fig.…”

Section: Methodsmentioning

confidence: 99%

Repurposing mesalazine against cardiac fibrosis in vitro

Hoffmann

Kant

Emig

et al. 2020

Naunyn-Schmiedeberg's Arch Pharmacol

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Cardiovascular diseases are exacerbated and driven by cardiac fibrosis. TGFβ induces fibroblast activation and differentiation into myofibroblasts that secrete excessive extracellular matrix proteins leading to stiffening of the heart, concomitant cardiac dysfunction, and arrhythmias. However, effective pharmacotherapy for preventing or reversing cardiac fibrosis is presently unavailable. Therefore, drug repurposing could be a cost- and time-saving approach to discover antifibrotic interventions. The aim of this study was to investigate the antifibrotic potential of mesalazine in a cardiac fibroblast stress model. TGFβ was used to induce a profibrotic phenotype in a human cardiac fibroblast cell line. After induction, cells were treated with mesalazine or solvent control. Fibroblast proliferation, key fibrosis protein expression, extracellular collagen deposition, and mechanical properties were subsequently determined. In response to TGFβ treatment, fibroblasts underwent a profound phenoconversion towards myofibroblasts, determined by the expression of fibrillary αSMA. Mesalazine reduced differentiation nearly by half and diminished fibroblast proliferation by a third. Additionally, TGFβ led to increased cell stiffness and adhesion, which were reversed by mesalazine treatment. Collagen 1 expression and deposition—key drivers of fibrosis—were significantly increased upon TGFβ stimulation and reduced to control levels by mesalazine. SMAD2/3 and ERK1/2 phosphorylation, along with reduced nuclear NFκB translocation, were identified as potential modes of action. The current study provides experimental pre-clinical evidence for antifibrotic effects of mesalazine in an in vitro model of cardiac fibrosis. Furthermore, it sheds light on possible mechanisms of action and suggests further investigation in experimental and clinical settings.

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“…Prior to stiffness measurements, cells were cultured on CyPhyGels for 4 days. These are hydrogels based on polyethylene glycol and the cyanobacterial photoreceptor Cph1* [Cph1-Y263F (amino acids 1-514)] allowing modulation of gel stiffness between 3 and 6 kPa by light [17,20].…”

Section: Cell Stiffnessmentioning

confidence: 99%

Modeling atrial fibrosis in vitro—Generation and characterization of a novel human atrial fibroblast cell line

et al. 2020

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Atrial fibrillation (AF) is regularly accompanied by cardiac fibrosis and concomitant heart failure. Due to the heterogeneous nature and complexity of fibrosis, the knowledge about the underlying mechanisms is limited, which prevents effective pharmacotherapy. A deeper understanding of cardiac fibroblasts is essential to meet this need. We previously described phenotypic and functional differences between atrial fibroblasts from patients in sinus rhythm and with AF. Herein, we established and characterized a novel human atrial fibroblast line, which displays typical fibroblast morphology and function comparable to primary cells but with improved proliferation capacity and low spontaneous myofibroblast differentiation. These traits make our model suitable for the study of fibrosis mechanisms and for drug screening aimed at developing effective antifibrotic pharmacotherapy. Cardiovascular diseases (CVD) such as heart failure and arrhythmia represent the leading cause of death worldwide [1,2]. A well-recognized concomitant of CVD is cardiac fibrosis [1], which is the structural manifestation of an imbalance in extracellular matrix (ECM) homeostasis. With nearly 45% of all deaths in the Western world attributable to fibroproliferative disease, the clinical relevance of fibrotic remodeling is enormous [3,4]. This is particularly true in the case of atrial fibrosis, associated with a detrimental clinical outcome of highly abundant supraventricular arrhythmias like atrial fibrillation (AF) [5]. However, due to

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Human Atrial Fibroblast Adaptation to Heterogeneities in Substrate Stiffness

Cited by 16 publications

References 34 publications

Piezo1 Channels Contribute to the Regulation of Human Atrial Fibroblast Mechanical Properties and Matrix Stiffness Sensing

Piezo1 Channels Contribute to the Regulation of Human Atrial Fibroblast Mechanical Properties and Matrix Stiffness Sensing

Repurposing mesalazine against cardiac fibrosis in vitro

Modeling atrial fibrosis in vitro—Generation and characterization of a novel human atrial fibroblast cell line

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