Biomechanical Signaling and Fibrosis

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

Deadline for manuscript submissions: closed (31 May 2021) | Viewed by 49323

Special Issue Editors


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Guest Editor
Biotech Research & Innovation Centre, The University of Copenhagen, Copenhagen, Denmark
Interests: Rho GTPases; keratinocytes; mouse disease models
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
Biotech Research & Innovation Centre, The University of Copenhagen, Copenhagen, Denmark
Interests: cardiac fibroblasts; fibrosis; biomechanical signalling; mechanotransduction; extracellular matrix

Special Issue Information

Dear Colleagues,

Fibrosis occurs in many different organs as part of various diseases and is involved in about 45% of all deaths. The detrimental effects of fibrosis are often linked to extensive stiffening of the affected tissues, which compromises organ function and affects cellular activity and function. Moreover, the pathological trigger for the development of fibrosis may also involve changes in mechanical properties, e.g., increased blood pressure. Thus, biomechanical signalling is a crucial, but not fully understood, part of fibrotic disease.

Biomechanical signalling can involve the activation of adhesion receptors and mechanosensitive ion channels in the plasma membrane. Cytoskeletal structure and organization affect intracellular signalling molecules and the translocation of transcription factors, thereby regulating fibrotic gene expression programs. Moreover, stiffness of the extracellular environment can affect gene regulation, cytoskeleton-mediated alteration of nuclear shape, chromatin organization and nuclear stiffness.

Whereas many different cell types are affected by fibrosis and tissue stiffening, the fibroblast is central for regulating the development of fibrosis. Fibroblasts are mechanosensitive cells, with great plasticity, that adjust their activity and phenotype according to mechanical signals. The subsequent remodelling of the extracellular matrix will change the mechanical properties of the extracellular environment. Thus, tissue-resident fibroblasts are constantly communicating and striving to obtain a mechanical balance with the surrounding matrix.

Importantly, efficient anti-fibrotic treatment is currently not available, possibly reflecting the lack of understanding of biomechanical signalling in fibrotic disease. This Special Issue will focus on biomechanical signalling mechanisms that regulate and respond to fibrosis in various organs during disease. In addition, in vitro, in vivo and in silico models of fibrotic disease and potential therapeutic strategies are of major interest.

Prof. Dr. Cord Brakebusch
Dr. Kate Møller Herum
Guest Editors

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Keywords

  • fibrosis
  • mechanotransduction
  • disease models
  • extracellular matrix
  • fibroblasts
  • mechanosensing
  • ion channels
  • Rho GTPase signalling
  • computational models

Published Papers (8 papers)

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Research

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10 pages, 1730 KiB  
Article
Piezo1 Mechanosensitive Ion Channel Mediates Stretch-Induced Nppb Expression in Adult Rat Cardiac Fibroblasts
by Meike C. Ploeg, Chantal Munts, Frits W. Prinzen, Neil A. Turner, Marc van Bilsen and Frans A. van Nieuwenhoven
Cells 2021, 10(7), 1745; https://doi.org/10.3390/cells10071745 - 9 Jul 2021
Cited by 13 | Viewed by 3478
Abstract
In response to stretch, cardiac tissue produces natriuretic peptides, which have been suggested to have beneficial effects in heart failure patients. In the present study, we explored the mechanism of stretch-induced brain natriuretic peptide (Nppb) expression in cardiac fibroblasts. Primary adult rat cardiac [...] Read more.
In response to stretch, cardiac tissue produces natriuretic peptides, which have been suggested to have beneficial effects in heart failure patients. In the present study, we explored the mechanism of stretch-induced brain natriuretic peptide (Nppb) expression in cardiac fibroblasts. Primary adult rat cardiac fibroblasts subjected to 4 h or 24 h of cyclic stretch (10% 1 Hz) showed a 6.6-fold or 3.2-fold (p < 0.05) increased mRNA expression of Nppb, as well as induction of genes related to myofibroblast differentiation. Moreover, BNP protein secretion was upregulated 5.3-fold in stretched cardiac fibroblasts. Recombinant BNP inhibited TGFβ1-induced Acta2 expression. Nppb expression was >20-fold higher in cardiomyocytes than in cardiac fibroblasts, indicating that cardiac fibroblasts were not the main source of Nppb in the healthy heart. Yoda1, an agonist of the Piezo1 mechanosensitive ion channel, increased Nppb expression 2.1-fold (p < 0.05) and significantly induced other extracellular matrix (ECM) remodeling genes. Silencing of Piezo1 reduced the stretch-induced Nppb and Tgfb1 expression in cardiac fibroblasts. In conclusion, our study identifies Piezo1 as mediator of stretch-induced Nppb expression, as well as other remodeling genes, in cardiac fibroblasts. Full article
(This article belongs to the Special Issue Biomechanical Signaling and Fibrosis)
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18 pages, 2287 KiB  
Article
Substrate Stiffness and Stretch Regulate Profibrotic Mechanosignaling in Pulmonary Arterial Adventitial Fibroblasts
by Ariel Wang, Shulin Cao, Jennifer C. Stowe and Daniela Valdez-Jasso
Cells 2021, 10(5), 1000; https://doi.org/10.3390/cells10051000 - 23 Apr 2021
Cited by 26 | Viewed by 4115
Abstract
Pulmonary arterial adventitial fibroblasts (PAAFs) are important regulators of fibrotic vascular remodeling during the progression of pulmonary arterial hypertension (PAH), a disease that currently has no effective anti-fibrotic treatments. We conducted in-vitro experiments in PAAFs cultured on hydrogels attached to custom-made equibiaxial stretchers [...] Read more.
Pulmonary arterial adventitial fibroblasts (PAAFs) are important regulators of fibrotic vascular remodeling during the progression of pulmonary arterial hypertension (PAH), a disease that currently has no effective anti-fibrotic treatments. We conducted in-vitro experiments in PAAFs cultured on hydrogels attached to custom-made equibiaxial stretchers at 10% stretch and substrate stiffnesses representing the mechanical conditions of mild and severe stages of PAH. The expression of collagens α(1)I and α(1)III and elastin messenger RNAs (Col1a1, Col3a1, Eln) were upregulated by increased stretch and substrate stiffness, while lysyl oxidase-like 1 and α-smooth muscle actin messenger RNAs (Loxl1, Acta2) were only significantly upregulated when the cells were grown on matrices with an elevated stiffness representative of mild PAH but not on a stiffness representative of severe PAH. Fibronectin messenger RNA (Fn1) levels were significantly induced by increased substrate stiffness and transiently upregulated by stretch at 4 h, but was not significantly altered by stretch at 24 h. We modified our published computational network model of the signaling pathways that regulate profibrotic gene expression in PAAFs to allow for differential regulation of mechanically-sensitive nodes by stretch and stiffness. When the model was modified so that stiffness activated integrin β3, the Macrophage Stimulating 1 or 2 (MST1\2) kinases, angiotensin II (Ang II), transforming growth factor-β (TGF-β), and syndecan-4, and stretch-regulated integrin β3, MST1\2, Ang II, and the transient receptor potential (TRP) channel, the model correctly predicted the upregulation of all six genes by increased stiffness and the observed responses to stretch in five out of six genes, although it could not replicate the non-monotonic effects of stiffness on Loxl1 and Acta2 expression. Blocking Ang II Receptor Type 1 (AT1R) with losartan in-vitro uncovered an interaction between the effects of stretch and stiffness and angiotensin-independent activation of Fn1 expression by stretch in PAAFs grown on 3-kPa matrices. This novel combination of in-vitro and in-silico models of PAAF profibrotic cell signaling in response to altered mechanical conditions may help identify regulators of vascular adventitial remodeling due to changes in stretch and matrix stiffness that occur during the progression of PAH in-vivo. Full article
(This article belongs to the Special Issue Biomechanical Signaling and Fibrosis)
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20 pages, 4441 KiB  
Article
Piezo1 Channels Contribute to the Regulation of Human Atrial Fibroblast Mechanical Properties and Matrix Stiffness Sensing
by Ramona Emig, Wiebke Knodt, Mario J. Krussig, Callum M. Zgierski-Johnston, Oliver Gorka, Olaf Groß, Peter Kohl, Ursula Ravens and Rémi Peyronnet
Cells 2021, 10(3), 663; https://doi.org/10.3390/cells10030663 - 16 Mar 2021
Cited by 52 | Viewed by 7149
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Biomechanical Signaling and Fibrosis)
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22 pages, 3857 KiB  
Article
Kindlin-2 Mediates Mechanical Activation of Cardiac Myofibroblasts
by Elena Godbout, Dong Ok Son, Stephanie Hume, Stellar Boo, Vincent Sarrazy, Sophie Clément, Andras Kapus, Bernhard Wehrle-Haller, Leena Bruckner-Tuderman, Cristina Has and Boris Hinz
Cells 2020, 9(12), 2702; https://doi.org/10.3390/cells9122702 - 17 Dec 2020
Cited by 11 | Viewed by 4059
Abstract
We identify the focal adhesion protein kindlin-2 as player in a novel mechanotransduction pathway that controls profibrotic cardiac fibroblast to myofibroblast activation. Kindlin-2 is co-upregulated with the myofibroblast marker α-smooth muscle actin (α-SMA) in fibrotic rat hearts and in human cardiac fibroblasts exposed [...] Read more.
We identify the focal adhesion protein kindlin-2 as player in a novel mechanotransduction pathway that controls profibrotic cardiac fibroblast to myofibroblast activation. Kindlin-2 is co-upregulated with the myofibroblast marker α-smooth muscle actin (α-SMA) in fibrotic rat hearts and in human cardiac fibroblasts exposed to fibrosis-stiff culture substrates and pro-fibrotic TGF-β1. Stressing fibroblasts using ferromagnetic microbeads, stretchable silicone membranes, and cell contraction agonists all result in kindlin-2 translocation to the nucleus. Overexpression of full-length kindlin-2 but not of kindlin-2 missing a putative nuclear localization sequence (∆NLS kindlin-2) results in increased α-SMA promoter activity. Downregulating kindlin-2 with siRNA leads to decreased myofibroblast contraction and reduced α-SMA expression, which is dependent on CC(A/T)-rich GG(CArG) box elements in the α-SMA promoter. Lost myofibroblast features under kindlin-2 knockdown are rescued with wild-type but not ∆NLS kindlin-2, indicating that myofibroblast control by kindlin-2 requires its nuclear translocation. Because kindlin-2 can act as a mechanotransducer regulating the transcription of α-SMA, it is a potential target to interfere with myofibroblast activation in tissue fibrosis. Full article
(This article belongs to the Special Issue Biomechanical Signaling and Fibrosis)
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Review

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14 pages, 2708 KiB  
Review
TRPV4 Mechanotransduction in Fibrosis
by Ravi K. Adapala, Venkatesh Katari, Lakshminarayan Reddy Teegala, Sathwika Thodeti, Sailaja Paruchuri and Charles K. Thodeti
Cells 2021, 10(11), 3053; https://doi.org/10.3390/cells10113053 - 6 Nov 2021
Cited by 18 | Viewed by 3798
Abstract
Fibrosis is an irreversible, debilitating condition marked by the excessive production of extracellular matrix and tissue scarring that eventually results in organ failure and disease. Differentiation of fibroblasts to hypersecretory myofibroblasts is the key event in fibrosis. Although both soluble and mechanical factors [...] Read more.
Fibrosis is an irreversible, debilitating condition marked by the excessive production of extracellular matrix and tissue scarring that eventually results in organ failure and disease. Differentiation of fibroblasts to hypersecretory myofibroblasts is the key event in fibrosis. Although both soluble and mechanical factors are implicated in fibroblast differentiation, much of the focus is on TGF-β signaling, but to date, there are no specific drugs available for the treatment of fibrosis. In this review, we describe the role for TRPV4 mechanotransduction in cardiac and lung fibrosis, and we propose TRPV4 as an alternative therapeutic target for fibrosis. Full article
(This article belongs to the Special Issue Biomechanical Signaling and Fibrosis)
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20 pages, 626 KiB  
Review
The Phenotypic Responses of Vascular Smooth Muscle Cells Exposed to Mechanical Cues
by Lise Filt Jensen, Jacob Fog Bentzon and Julian Albarrán-Juárez
Cells 2021, 10(9), 2209; https://doi.org/10.3390/cells10092209 - 26 Aug 2021
Cited by 30 | Viewed by 8319
Abstract
During the development of atherosclerosis and other vascular diseases, vascular smooth muscle cells (SMCs) located in the intima and media of blood vessels shift from a contractile state towards other phenotypes that differ substantially from differentiated SMCs. In addition, these cells acquire new [...] Read more.
During the development of atherosclerosis and other vascular diseases, vascular smooth muscle cells (SMCs) located in the intima and media of blood vessels shift from a contractile state towards other phenotypes that differ substantially from differentiated SMCs. In addition, these cells acquire new functions, such as the production of alternative extracellular matrix (ECM) proteins and signal molecules. A similar shift in cell phenotype is observed when SMCs are removed from their native environment and placed in a culture, presumably due to the absence of the physiological signals that maintain and regulate the SMC phenotype in the vasculature. The far majority of studies describing SMC functions have been performed under standard culture conditions in which cells adhere to a rigid and static plastic plate. While these studies have contributed to discovering key molecular pathways regulating SMCs, they have a significant limitation: the ECM microenvironment and the mechanical forces transmitted through the matrix to SMCs are generally not considered. Here, we review and discuss the recent literature on how the mechanical forces and derived biochemical signals have been shown to modulate the vascular SMC phenotype and provide new perspectives about their importance. Full article
(This article belongs to the Special Issue Biomechanical Signaling and Fibrosis)
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26 pages, 3794 KiB  
Review
Implant Fibrosis and the Underappreciated Role of Myofibroblasts in the Foreign Body Reaction
by Nina Noskovicova, Boris Hinz and Pardis Pakshir
Cells 2021, 10(7), 1794; https://doi.org/10.3390/cells10071794 - 15 Jul 2021
Cited by 64 | Viewed by 10566
Abstract
Body implants and implantable medical devices have dramatically improved and prolonged the life of countless patients. However, our body repair mechanisms have evolved to isolate, reject, or destroy any object that is recognized as foreign to the organism and inevitably mounts a foreign [...] Read more.
Body implants and implantable medical devices have dramatically improved and prolonged the life of countless patients. However, our body repair mechanisms have evolved to isolate, reject, or destroy any object that is recognized as foreign to the organism and inevitably mounts a foreign body reaction (FBR). Depending on its severity and chronicity, the FBR can impair implant performance or create severe clinical complications that will require surgical removal and/or replacement of the faulty device. The number of review articles discussing the FBR seems to be proportional to the number of different implant materials and clinical applications and one wonders, what else is there to tell? We will here take the position of a fibrosis researcher (which, coincidentally, we are) to elaborate similarities and differences between the FBR, normal wound healing, and chronic healing conditions that result in the development of peri-implant fibrosis. After giving credit to macrophages in the inflammatory phase of the FBR, we will mainly focus on the activation of fibroblastic cells into matrix-producing and highly contractile myofibroblasts. While fibrosis has been discussed to be a consequence of the disturbed and chronic inflammatory milieu in the FBR, direct activation of myofibroblasts at the implant surface is less commonly considered. Thus, we will provide a perspective how physical properties of the implant surface control myofibroblast actions and accumulation of stiff scar tissue. Because formation of scar tissue at the surface and around implant materials is a major reason for device failure and extraction surgeries, providing implant surfaces with myofibroblast-suppressing features is a first step to enhance implant acceptance and functional lifetime. Alternative therapeutic targets are elements of the myofibroblast mechanotransduction and contractile machinery and we will end with a brief overview on such targets that are considered for the treatment of other organ fibroses. Full article
(This article belongs to the Special Issue Biomechanical Signaling and Fibrosis)
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34 pages, 3118 KiB  
Review
Channelling the Force to Reprogram the Matrix: Mechanosensitive Ion Channels in Cardiac Fibroblasts
by Leander Stewart and Neil A. Turner
Cells 2021, 10(5), 990; https://doi.org/10.3390/cells10050990 - 23 Apr 2021
Cited by 45 | Viewed by 6673
Abstract
Cardiac fibroblasts (CF) play a pivotal role in preserving myocardial function and integrity of the heart tissue after injury, but also contribute to future susceptibility to heart failure. CF sense changes to the cardiac environment through chemical and mechanical cues that trigger changes [...] Read more.
Cardiac fibroblasts (CF) play a pivotal role in preserving myocardial function and integrity of the heart tissue after injury, but also contribute to future susceptibility to heart failure. CF sense changes to the cardiac environment through chemical and mechanical cues that trigger changes in cellular function. In recent years, mechanosensitive ion channels have been implicated as key modulators of a range of CF functions that are important to fibrotic cardiac remodelling, including cell proliferation, myofibroblast differentiation, extracellular matrix turnover and paracrine signalling. To date, seven mechanosensitive ion channels are known to be functional in CF: the cation non-selective channels TRPC6, TRPM7, TRPV1, TRPV4 and Piezo1, and the potassium-selective channels TREK-1 and KATP. This review will outline current knowledge of these mechanosensitive ion channels in CF, discuss evidence of the mechanosensitivity of each channel, and detail the role that each channel plays in cardiac remodelling. By better understanding the role of mechanosensitive ion channels in CF, it is hoped that therapies may be developed for reducing pathological cardiac remodelling. Full article
(This article belongs to the Special Issue Biomechanical Signaling and Fibrosis)
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