Philosophical Transactions of the Royal Society B: Biological Sciences
The stiffness of the cardiovascular environment changes during ageing and in disease and contribu... more The stiffness of the cardiovascular environment changes during ageing and in disease and contributes to disease incidence and progression. Changing collagen expression and cross-linking regulate the rigidity of the cardiac extracellular matrix (ECM). Additionally, basal lamina glycoproteins, especially laminin and fibronectin regulate cardiomyocyte adhesion formation, mechanics and mechanosignalling. Laminin is abundant in the healthy heart, but fibronectin is increasingly expressed in the fibrotic heart. ECM receptors are co-regulated with the changing ECM. Owing to differences in integrin dynamics, clustering and downstream adhesion formation this is expected to ultimately influence cardiomyocyte mechanosignalling; however, details remain elusive. Here, we sought to investigate how different cardiomyocyte integrin/ligand combinations affect adhesion formation, traction forces and mechanosignalling, using a combination of uniformly coated surfaces with defined stiffness, polydimeth...
Vascular smooth muscle cells (VSMCs) play a central role in the progression of atherosclerosis, w... more Vascular smooth muscle cells (VSMCs) play a central role in the progression of atherosclerosis, where they switch from a contractile to a synthetic phenotype. Because of their role as risk factors for atherosclerosis, we sought here to systematically study the impact of matrix stiffness and (hemodynamic) pressure on VSMCs. Thereby, we find that pressure and stiffness individually affect the VSMC phenotype. However, only the combination of hypertensive pressure and matrix compliance, and as such mechanical stimuli that are prevalent during atherosclerosis, leads to a full phenotypic switch including the formation of matrix-degrading podosomes. We further analyze the molecular mechanism in stiffness and pressure sensing and identify a regulation through different but overlapping pathways culminating in the regulation of the actin cytoskeleton through cofilin. Together, our data show how different pathological mechanical signals combined but through distinct pathways accelerate a pheno...
Nuclear envelope integrity is essential for compartmentalisation of nucleus and cytoplasm. Import... more Nuclear envelope integrity is essential for compartmentalisation of nucleus and cytoplasm. Importantly, mutations in nuclear envelope-encoding genes are the second-highest cause of familial dilated cardiomyopathy. One such nuclear envelope protein that causes cardiomyopathy in humans and affects mouse heart development is Lem2. However, its role in mechanically active tissue such as heart remains poorly understood.We generated mice in which Lem2 was specifically ablated in cardiomyocytes and carried out detailed physiological, tissue and cellular analyses. Importantly, our data showed that Lem2 was essential for cardiac development, and hearts from Lem2 cKO mice were morphologically and transcriptionally underdeveloped. Lem2 cKO hearts displayed high levels of DNA damage, nuclear rupture, and apoptosis. Crucially, we found that these defects were driven by muscle contraction as they were ameliorated by inhibiting myosin contraction and conversely were exacerbated upon myosin activat...
This is an Open Access article distributed under the terms of the Creative Commons Attribution Li... more This is an Open Access article distributed under the terms of the Creative Commons Attribution License
The stiffness of the cardiovascular environment changes during ageing and in disease and contribu... more The stiffness of the cardiovascular environment changes during ageing and in disease and contributes to disease incidence and progression. Changing collagen expression and crosslinking regulate the rigidity of the cardiac ECM. Additionally, basal lamina glycoproteins, especially laminin and fibronectin regulate cardiomyocyte adhesion formation, mechanics and mechano-signalling. Laminin is abundant in the healthy heart, but fibronectin is increasingly expressed in the fibrotic heart. ECM receptors are co-regulated with the changing ECM. Due to differences in integrin dynamics, clustering, and downstream adhesion formation this is expected to ultimately influence cardiomyocyte mechanosignalling; however details remain elusive. Here we sought to investigate how different cardiomyocyte ligand/integrin combinations are affecting adhesion formation, traction forces and mechanosignalling, using a combination of uniformly coated surfaces with defined stiffness, PDMS nanopillars, micropatter...
eIF6 is known for its role as a stimulatory translation initiation factor. In this issue, Keen et... more eIF6 is known for its role as a stimulatory translation initiation factor. In this issue, Keen et al. (2022. J. Cell Biol. https://doi.org/10.1083/jcb.202005213) identify a novel, noncanonical role, whereby eIF6 regulates focal adhesion formation, mechanosensing, and cell mechanics, independent of its translational role.
Additional file 1: Figure S1. Atomic Force Microscopy force-volume maps. (A, B, C, D) 3D reconstr... more Additional file 1: Figure S1. Atomic Force Microscopy force-volume maps. (A, B, C, D) 3D reconstructions of height of the contact point of control, 0.0015% w/w of MWCNT, 0.00625% w/w and 0.05% w/w samples, respectively. Histograms of the associated Young's modulus E fitted with a Gaussian distribution. Stiffness values given in the text correspond to the mean ± SD of 5 independent elasticity maps. Statistical significance was determined using one-way ANOVA with post hoc Tukey's Honest Significant Difference test for multiple comparisons. P values of less than 0.05 were considered significant. (D) 3D-reconstruction of the contact point's height. Figure S2. Western Blot quantification of WT GSC proteins expression. Each western blot quantification was performed three to seven times and normalized with respect to GAPDH expressions and sum. Bands were quantified using the Bio-Rad Chemidoc and the image lab software. Data are presented as mean +/− SEM and statistical signific...
This Commentary describes a call for submissions for the upcoming special issue focused on the st... more This Commentary describes a call for submissions for the upcoming special issue focused on the state of the art of cardiovascular mechanobiology research and the newest insights into the role of mechanical forces in cardiovascular development, physiology, and disease.
Vascular smooth muscle cells (VSMCs) play a central role in the onset and progression of atherosc... more Vascular smooth muscle cells (VSMCs) play a central role in the onset and progression of atherosclerosis. In pre-atherosclerotic lesions, VSMCs switch from a contractile to a synthetic phenotype and subsequently remodel the microenvironment, leading to further disease progression. Ageing and associated mechanical changes of the extracellular matrix as well as hypertension are major risk of atherosclerosis. Consequently, we sought here to systematically study the impact of mechanical stimulations on VSMC phenotypic switching, by modulating both stiffness and hydrodynamic pressure. Thereby we find that hemodynamic pressure and matrix stiffness individually affect the VSMC phenotype. However, only the combination of hypertensive pressure and matrix compliance, and as such mechanical stimuli that are prevalent during atherosclerosis, lead to a full phenotypic switch including the formation of matrix degrading podosomes. We further analyse the molecular mechanism in stiffness and pressur...
Cardiomyocytes generate force for the contraction of the heart to pump blood into the lungs and b... more Cardiomyocytes generate force for the contraction of the heart to pump blood into the lungs and body. At the same time, they are exquisitely tuned to the mechanical environment and react to e.g. changes in cell and extracellular matrix stiffness or altered stretching due to reduced ejection fraction in heart disease, by adapting their cytoskeleton, force generation and cell mechanics. Both mechanical sensing and cell mechanical adaptations are multiscale processes. Receptor interactions with the extracellular matrix at the nanoscale will lead to clustering of receptors and modification of the cytoskeleton. This in turn alters mechanosensing, force generation, cell and nuclear stiffness and viscoelasticity at the microscale. Further, this affects cell shape, orientation, maturation and tissue integration at the microscale to macroscale. A variety of tools have been developed and adapted to measure cardiomyocyte receptor-ligand interactions and forces or mechanics at the different ran...
Glioblastomas stem-like cells (GSCs) by invading the brain parenchyma escape resection and radiot... more Glioblastomas stem-like cells (GSCs) by invading the brain parenchyma escape resection and radiotherapy. GSC invasion is associated with altered N-glycosylation pattern of integrins and other transmembrane proteins resulting in changed mechanosensing but details are elusive. Because the tumour microenvironment has an increased stiffness we studied the interaction between matrix stiffness, N-glycosylation and GSC migration. To mimic the fibrillar microenvironments, we designed 3D-ex-polyacrylonitrile nanofibers scaffolds (NFS) with adjustable stiffnesses by loading multiwall carbon nanotubes (MWCNT). We found that migration of GSCs was maximum at 166 kPa. Migration rate was correlated with cell shape, expression of focal adhesion (FA), Epithelial to Mesenchymal Transition (EMT) proteins and (β1,6) branched N-glycan binding, galectin-3. Mutation of MGAT5 in GSC inhibited N-glycans (β1–6) branching, suppressed the stiffness dependence of FA and EMT protein expression as well as migrati...
Nanoscale organisation of receptor ligands has become an important approach to study the clusteri... more Nanoscale organisation of receptor ligands has become an important approach to study the clustering behaviour of cell-surface receptors. Biomimetic substrates fabricated via different nanopatterning strategies have so far been applied...
In this issue of Developmental Cell, Cho et al. (2019) find that lamin-A levels in the nuclear en... more In this issue of Developmental Cell, Cho et al. (2019) find that lamin-A levels in the nuclear envelope are regulated in response to mechanical stimuli to prevent the nucleus from rupture, keep DNA repair factors in the nucleus, and consequentially "mechano-protect the genome."
Philosophical Transactions of the Royal Society B: Biological Sciences
The stiffness of the cardiovascular environment changes during ageing and in disease and contribu... more The stiffness of the cardiovascular environment changes during ageing and in disease and contributes to disease incidence and progression. Changing collagen expression and cross-linking regulate the rigidity of the cardiac extracellular matrix (ECM). Additionally, basal lamina glycoproteins, especially laminin and fibronectin regulate cardiomyocyte adhesion formation, mechanics and mechanosignalling. Laminin is abundant in the healthy heart, but fibronectin is increasingly expressed in the fibrotic heart. ECM receptors are co-regulated with the changing ECM. Owing to differences in integrin dynamics, clustering and downstream adhesion formation this is expected to ultimately influence cardiomyocyte mechanosignalling; however, details remain elusive. Here, we sought to investigate how different cardiomyocyte integrin/ligand combinations affect adhesion formation, traction forces and mechanosignalling, using a combination of uniformly coated surfaces with defined stiffness, polydimeth...
Vascular smooth muscle cells (VSMCs) play a central role in the progression of atherosclerosis, w... more Vascular smooth muscle cells (VSMCs) play a central role in the progression of atherosclerosis, where they switch from a contractile to a synthetic phenotype. Because of their role as risk factors for atherosclerosis, we sought here to systematically study the impact of matrix stiffness and (hemodynamic) pressure on VSMCs. Thereby, we find that pressure and stiffness individually affect the VSMC phenotype. However, only the combination of hypertensive pressure and matrix compliance, and as such mechanical stimuli that are prevalent during atherosclerosis, leads to a full phenotypic switch including the formation of matrix-degrading podosomes. We further analyze the molecular mechanism in stiffness and pressure sensing and identify a regulation through different but overlapping pathways culminating in the regulation of the actin cytoskeleton through cofilin. Together, our data show how different pathological mechanical signals combined but through distinct pathways accelerate a pheno...
Nuclear envelope integrity is essential for compartmentalisation of nucleus and cytoplasm. Import... more Nuclear envelope integrity is essential for compartmentalisation of nucleus and cytoplasm. Importantly, mutations in nuclear envelope-encoding genes are the second-highest cause of familial dilated cardiomyopathy. One such nuclear envelope protein that causes cardiomyopathy in humans and affects mouse heart development is Lem2. However, its role in mechanically active tissue such as heart remains poorly understood.We generated mice in which Lem2 was specifically ablated in cardiomyocytes and carried out detailed physiological, tissue and cellular analyses. Importantly, our data showed that Lem2 was essential for cardiac development, and hearts from Lem2 cKO mice were morphologically and transcriptionally underdeveloped. Lem2 cKO hearts displayed high levels of DNA damage, nuclear rupture, and apoptosis. Crucially, we found that these defects were driven by muscle contraction as they were ameliorated by inhibiting myosin contraction and conversely were exacerbated upon myosin activat...
This is an Open Access article distributed under the terms of the Creative Commons Attribution Li... more This is an Open Access article distributed under the terms of the Creative Commons Attribution License
The stiffness of the cardiovascular environment changes during ageing and in disease and contribu... more The stiffness of the cardiovascular environment changes during ageing and in disease and contributes to disease incidence and progression. Changing collagen expression and crosslinking regulate the rigidity of the cardiac ECM. Additionally, basal lamina glycoproteins, especially laminin and fibronectin regulate cardiomyocyte adhesion formation, mechanics and mechano-signalling. Laminin is abundant in the healthy heart, but fibronectin is increasingly expressed in the fibrotic heart. ECM receptors are co-regulated with the changing ECM. Due to differences in integrin dynamics, clustering, and downstream adhesion formation this is expected to ultimately influence cardiomyocyte mechanosignalling; however details remain elusive. Here we sought to investigate how different cardiomyocyte ligand/integrin combinations are affecting adhesion formation, traction forces and mechanosignalling, using a combination of uniformly coated surfaces with defined stiffness, PDMS nanopillars, micropatter...
eIF6 is known for its role as a stimulatory translation initiation factor. In this issue, Keen et... more eIF6 is known for its role as a stimulatory translation initiation factor. In this issue, Keen et al. (2022. J. Cell Biol. https://doi.org/10.1083/jcb.202005213) identify a novel, noncanonical role, whereby eIF6 regulates focal adhesion formation, mechanosensing, and cell mechanics, independent of its translational role.
Additional file 1: Figure S1. Atomic Force Microscopy force-volume maps. (A, B, C, D) 3D reconstr... more Additional file 1: Figure S1. Atomic Force Microscopy force-volume maps. (A, B, C, D) 3D reconstructions of height of the contact point of control, 0.0015% w/w of MWCNT, 0.00625% w/w and 0.05% w/w samples, respectively. Histograms of the associated Young's modulus E fitted with a Gaussian distribution. Stiffness values given in the text correspond to the mean ± SD of 5 independent elasticity maps. Statistical significance was determined using one-way ANOVA with post hoc Tukey's Honest Significant Difference test for multiple comparisons. P values of less than 0.05 were considered significant. (D) 3D-reconstruction of the contact point's height. Figure S2. Western Blot quantification of WT GSC proteins expression. Each western blot quantification was performed three to seven times and normalized with respect to GAPDH expressions and sum. Bands were quantified using the Bio-Rad Chemidoc and the image lab software. Data are presented as mean +/− SEM and statistical signific...
This Commentary describes a call for submissions for the upcoming special issue focused on the st... more This Commentary describes a call for submissions for the upcoming special issue focused on the state of the art of cardiovascular mechanobiology research and the newest insights into the role of mechanical forces in cardiovascular development, physiology, and disease.
Vascular smooth muscle cells (VSMCs) play a central role in the onset and progression of atherosc... more Vascular smooth muscle cells (VSMCs) play a central role in the onset and progression of atherosclerosis. In pre-atherosclerotic lesions, VSMCs switch from a contractile to a synthetic phenotype and subsequently remodel the microenvironment, leading to further disease progression. Ageing and associated mechanical changes of the extracellular matrix as well as hypertension are major risk of atherosclerosis. Consequently, we sought here to systematically study the impact of mechanical stimulations on VSMC phenotypic switching, by modulating both stiffness and hydrodynamic pressure. Thereby we find that hemodynamic pressure and matrix stiffness individually affect the VSMC phenotype. However, only the combination of hypertensive pressure and matrix compliance, and as such mechanical stimuli that are prevalent during atherosclerosis, lead to a full phenotypic switch including the formation of matrix degrading podosomes. We further analyse the molecular mechanism in stiffness and pressur...
Cardiomyocytes generate force for the contraction of the heart to pump blood into the lungs and b... more Cardiomyocytes generate force for the contraction of the heart to pump blood into the lungs and body. At the same time, they are exquisitely tuned to the mechanical environment and react to e.g. changes in cell and extracellular matrix stiffness or altered stretching due to reduced ejection fraction in heart disease, by adapting their cytoskeleton, force generation and cell mechanics. Both mechanical sensing and cell mechanical adaptations are multiscale processes. Receptor interactions with the extracellular matrix at the nanoscale will lead to clustering of receptors and modification of the cytoskeleton. This in turn alters mechanosensing, force generation, cell and nuclear stiffness and viscoelasticity at the microscale. Further, this affects cell shape, orientation, maturation and tissue integration at the microscale to macroscale. A variety of tools have been developed and adapted to measure cardiomyocyte receptor-ligand interactions and forces or mechanics at the different ran...
Glioblastomas stem-like cells (GSCs) by invading the brain parenchyma escape resection and radiot... more Glioblastomas stem-like cells (GSCs) by invading the brain parenchyma escape resection and radiotherapy. GSC invasion is associated with altered N-glycosylation pattern of integrins and other transmembrane proteins resulting in changed mechanosensing but details are elusive. Because the tumour microenvironment has an increased stiffness we studied the interaction between matrix stiffness, N-glycosylation and GSC migration. To mimic the fibrillar microenvironments, we designed 3D-ex-polyacrylonitrile nanofibers scaffolds (NFS) with adjustable stiffnesses by loading multiwall carbon nanotubes (MWCNT). We found that migration of GSCs was maximum at 166 kPa. Migration rate was correlated with cell shape, expression of focal adhesion (FA), Epithelial to Mesenchymal Transition (EMT) proteins and (β1,6) branched N-glycan binding, galectin-3. Mutation of MGAT5 in GSC inhibited N-glycans (β1–6) branching, suppressed the stiffness dependence of FA and EMT protein expression as well as migrati...
Nanoscale organisation of receptor ligands has become an important approach to study the clusteri... more Nanoscale organisation of receptor ligands has become an important approach to study the clustering behaviour of cell-surface receptors. Biomimetic substrates fabricated via different nanopatterning strategies have so far been applied...
In this issue of Developmental Cell, Cho et al. (2019) find that lamin-A levels in the nuclear en... more In this issue of Developmental Cell, Cho et al. (2019) find that lamin-A levels in the nuclear envelope are regulated in response to mechanical stimuli to prevent the nucleus from rupture, keep DNA repair factors in the nucleus, and consequentially "mechano-protect the genome."
Uploads