Mechanical regulation of cardiac fibroblast profibrotic phenotypes

Herum, Kate M.; Choppe, Jonas; Kumar, Aditya; Engler, Adam J.; McCulloch, Andrew D.

doi:10.1091/mbc.e17-01-0014

Cited by 171 publications

(185 citation statements)

References 75 publications

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Section: Cardiac Fibroblasts and Mechanotransductionmentioning

confidence: 98%

“…An example of the latter was recently demonstrated by our group showing an increase in cardiac fibroblast proliferation when cultured in the same media as stretched cardiomyocytes [39]. Persistent elevated stretch of cardiac fibroblasts stimulates sustained production of ECM [39,62] causing myocardial stiffening. Interestingly, stretch-induced transcription of certain ECM genes is dependent on matrix stiffness; i.e., cardiac fibroblasts cultured on 3 kPa substrates display different stretch responses than cardiac fibroblasts on 8 kPa substrates [39].…”

Section: Cardiac Fibroblasts and Mechanotransductionmentioning

confidence: 98%

See 1 more Smart Citation

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

Herum

Lunde

McCulloch

et al. 2017

JCM

140

123

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Cardiac fibrosis, the excessive accumulation of extracellular matrix (ECM), remains an unresolved problem in most forms of heart disease. In order to be successful in preventing, attenuating or reversing cardiac fibrosis, it is essential to understand the processes leading to ECM production and accumulation. Cardiac fibroblasts are the main producers of cardiac ECM, and harbor great phenotypic plasticity. They are activated by the disease-associated changes in mechanical properties of the heart, including stretch and increased tissue stiffness. Despite much remaining unknown, an interesting body of evidence exists on how mechanical forces are translated into transcriptional responses important for determination of fibroblast phenotype and production of ECM constituents. Such mechanotransduction can occur at multiple cellular locations including the plasma membrane, cytoskeleton and nucleus. Moreover, the ECM functions as a reservoir of pro-fibrotic signaling molecules that can be released upon mechanical stress. We here review the current status of knowledge of mechanotransduction signaling pathways in cardiac fibroblasts that culminate in pro-fibrotic gene expression.

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Section: Cardiac Fibroblasts and Mechanotransductionmentioning

confidence: 98%

Section: Cardiac Fibroblasts and Mechanotransductionmentioning

confidence: 98%

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

Herum

Lunde

McCulloch

et al. 2017

JCM

140

123

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“…Substrate stiffness is known to influence cell morphology in av ariety of cell types,i ncluding CFbs. [3] To elucidate whether CFbs would respond to stiffening PEG-Ant hydrogels over the selected range,w ef irst measured cell area and nuclear roundness up to 5days post-stiffening.F igure 3b shows that in situ stiffening from 10 to 50 kPa resulted in ag radual increase in cell area from 1000 to 3200 mm 2 and ad ecrease in nuclear roundness from 0.92 to 0.73, whereas neither of these cell features changed significantly on the 10 kPa static hydrogels.I ti sw ell known that on stiff hydrogels,cells tend to become more spread over the surface of the hydrogel, resulting in an increase in cell area, and the cell and nuclear morphology becomes more elongated, causing ad ecrease in nuclear roundness.C ollectively,t hese results indicate the cytocompatibility of the dimerization/ hydrogel stiffening reaction, and that the CFbs respond to changes in the hydrogel modulus over the selected range.…”

Section: Zuschriftenmentioning

confidence: 99%

“…[2] As one example,c ardiac fibroblasts (CFbs) can respond to increased ECM stiffness and transform from aquiescent phenotype into an activated myofibroblast. [3] The wound-healing myofibroblast exhibits enhanced secretion of ECM proteins,such as collagen, which can further stiffen the cardiac tissue,p erpetuating further myofibroblast activation and eventually leading to long-term cardiac fibrosis. [4] While CFbs respond to changes in the tissue modulus,c ellular mechanisms involved in sensing and responding to stiffness remain elusive.…”

mentioning

confidence: 99%

PEG–Anthracene Hydrogels as an On‐Demand Stiffening Matrix To Study Mechanobiology

et al. 2019

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There is ag rowing interest in materials that can dynamically change their properties in the presence of cells to study mechanobiology.H erein, we exploit the 365 nm light mediated [4+ +4] photodimerization of anthracene groups to develop cytocompatible PEG-based hydrogels with tailorable initial moduli that can be further stiffened. Ah ydrogel formulation that can stiffen from 10 to 50 kPa, corresponding to the stiffness of ahealthy and fibrotic heart, respectively,was prepared. This system was used to monitor the stiffnessdependent localization of NFAT,adownstream target of intracellular calcium signaling using ar eporter in live cardiac fibroblasts (CFbs). NFAT translocates to the nucleus of CFbs on stiffening hydrogels within 6h,w hereas it remains cytoplasmic when the CFbs are cultured on either 10 or 50 kPa static hydrogels.T his finding demonstrates howd ynamic changes in the mechanical properties of am aterial can reveal the kinetics of mechanoresponsive cell signaling pathwaysthat may otherwise be missed in cells cultured on static substrates.

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“…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).…”

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

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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...

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Mechanical regulation of cardiac fibroblast profibrotic phenotypes

Cited by 171 publications

References 75 publications

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

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

PEG–Anthracene Hydrogels as an On‐Demand Stiffening Matrix To Study Mechanobiology

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

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