The Mechanical Contribution of Vimentin to Cellular Stress Generation

Loosdregt, I.A.E.W. van; Weissenberger, Giulia; Maris, M.P.F.H.L. van; Oomens, C.W.J.; Loerakker, Sandra; Stassen, Oscar M. J. A.; Bouten, Cvc Carlijn

doi:10.1115/1.4039308

Cited by 10 publications

(11 citation statements)

References 35 publications

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“…Thus, depletion of vimentin filaments can cause instability of the microtubule network, thereby increasing contractility and traction forces (Figure S17B). This prediction agrees well with experimental studies in the literature for fibroblasts on stiff substrates where VIF -/-cells generate significantly higher forces compared with VIF +/+ cells (20)(21)(22). In contrast, microtubules in cells on soft substrates experience low co mpression, and therefore depletion of vimentin filaments does not cause significant instability in the microtubule network (Figure S17A).…”

Section: Discussionsupporting

confidence: 90%

“…While the roles of the actin and microtubule networks in the generation and transmission of internal forces are known, it is not clear if and how intermediate filaments impact cellular forces. For example, experimental studies in the literature on fibroblasts, which are the most common cell type in connective tissues, report three different scenarios; upon depletion of vimentin intermediate filaments in fibroblasts, cell tractions forces have been observed (i) to decrease (17)(18)(19), (ii) to increase (20)(21)(22), or (iii) to remain the same (23). This discrepancy calls into question the role of vimentin intermediate filaments in the transmission of internally generated contractile forces to the ECM.…”

Section: Introductionmentioning

confidence: 99%

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Vimentin Intermediate Filaments Can Enhance or Abate Active Cellular Forces in a Microenvironmental Stiffness-Dependent Manner

Alisafaei

Mandal

Swoger

et al. 2022

Preprint

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The mechanical properties of cells are largely determined by the cytoskeleton, which is a complex network of interconnected biopolymers consisting of actin filaments, microtubules, and intermediate filaments. While disruption of the actin filament and microtubule networks is known to decrease and increase cell-generated forces, respectively, the effect of intermediate filaments on cellular forces is not well understood. Using a combination of theoretical modeling and experiments, we show that disruption of vimentin intermediate filaments can either increase or decrease cell-generated forces, depending on microenvironment stiffness, reconciling seemingly opposite results in the literature. On the one hand, vimentin is involved in the transmission of actomyosin-based tensile forces to the matrix and therefore enhances traction forces. On the other hand, vimentin reinforces microtubules and their stability under compression, thus promoting the role of microtubules in suppressing cellular traction forces. We show that the competition between these two opposing effects of vimentin is regulated by the microenvironment stiffness. For low matrix stiffness, the force-transmitting role of vimentin dominates over their microtubule-reinforcing role and therefore vimentin increases traction forces. At high matrix stiffness, vimentin decreases traction forces as the microtubule-reinforcing role of vimentin becomes more important with increasing matrix stiffness. Our theory reconciles seemingly disparate experimental observations on the role of vimentin in active cellular forces and provides a unified description of stiffness-dependent chemo-mechanical regulation of cell contractility by vimentin.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Vimentin Intermediate Filaments Can Enhance or Abate Active Cellular Forces in a Microenvironmental Stiffness-Dependent Manner

Alisafaei

Mandal

Swoger

et al. 2022

Preprint

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“…This indicates that the method used to alter vimentin can influence the response, as described earlier by Charrier and Janmey [ 150 ]. Although a number of studies have indicated that vimentin is important for generation of contractile forces in cells [ 143 , 144 ], a recent study reported that the loss of vimentin increased the generation of contractile stress 3-fold [ 146 ]. Moreover, the viscous responses of cells have been suggested to depend upon vimentin [ 151 ].…”

Section: Vimentin: Functionmentioning

confidence: 99%

Vimentin Diversity in Health and Disease

Danielsson

Peterson

Araújo

et al. 2018

Cells

210

204

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Vimentin is a protein that has been linked to a large variety of pathophysiological conditions, including cataracts, Crohn’s disease, rheumatoid arthritis, HIV and cancer. Vimentin has also been shown to regulate a wide spectrum of basic cellular functions. In cells, vimentin assembles into a network of filaments that spans the cytoplasm. It can also be found in smaller, non-filamentous forms that can localise both within cells and within the extracellular microenvironment. The vimentin structure can be altered by subunit exchange, cleavage into different sizes, re-annealing, post-translational modifications and interacting proteins. Together with the observation that different domains of vimentin might have evolved under different selection pressures that defined distinct biological functions for different parts of the protein, the many diverse variants of vimentin might be the cause of its functional diversity. A number of review articles have focussed on the biology and medical aspects of intermediate filament proteins without particular commitment to vimentin, and other reviews have focussed on intermediate filaments in an in vitro context. In contrast, the present review focusses almost exclusively on vimentin, and covers both ex vivo and in vivo data from tissue culture and from living organisms, including a summary of the many phenotypes of vimentin knockout animals. Our aim is to provide a comprehensive overview of the current understanding of the many diverse aspects of vimentin, from biochemical, mechanical, cellular, systems biology and medical perspectives.

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“…In particular, modification of the mechanical microenvironment resulted in a transient reduction in RPC adhesion and spreading capacity, a phenomenon described in other cell types [ 53 ]. Notably, recent studies have demonstrated that vimentin, which contributes to cells resilience against mechanical stress [ 54 ], generates with actin and microtubules the forces required for cell adhesion. More specifically, vimentin regulates stress generation by adherent cells through an interplay with actin stress fibers [ 55 ].…”

Section: Discussionmentioning

confidence: 99%

Modeled microgravity unravels the roles of mechanical forces in renal progenitor cell physiology

Melica,

Cialdai,

La Regina

et al. 2024

Stem Cell Res Ther

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Background The glomerulus is a highly complex system, composed of different interdependent cell types that are subjected to various mechanical stimuli. These stimuli regulate multiple cellular functions, and changes in these functions may contribute to tissue damage and disease progression. To date, our understanding of the mechanobiology of glomerular cells is limited, with most research focused on the adaptive response of podocytes. However, it is crucial to recognize the interdependence between podocytes and parietal epithelial cells, in particular with the progenitor subset, as it plays a critical role in various manifestations of glomerular diseases. This highlights the necessity to implement the analysis of the effects of mechanical stress on renal progenitor cells. Methods Microgravity, modeled by Rotary Cell Culture System, has been employed as a system to investigate how renal progenitor cells respond to alterations in the mechanical cues within their microenvironment. Changes in cell phenotype, cytoskeleton organization, cell proliferation, cell adhesion and cell capacity for differentiation into podocytes were analyzed. Results In modeled microgravity conditions, renal progenitor cells showed altered cytoskeleton and focal adhesion organization associated with a reduction in cell proliferation, cell adhesion and spreading capacity. Moreover, mechanical forces appeared to be essential for renal progenitor differentiation into podocytes. Indeed, when renal progenitors were exposed to a differentiative agent in modeled microgravity conditions, it impaired the acquisition of a complex podocyte-like F-actin cytoskeleton and the expression of specific podocyte markers, such as nephrin and nestin. Importantly, the stabilization of the cytoskeleton with a calcineurin inhibitor, cyclosporine A, rescued the differentiation of renal progenitor cells into podocytes in modeled microgravity conditions. Conclusions Alterations in the organization of the renal progenitor cytoskeleton due to unloading conditions negatively affect the regenerative capacity of these cells. These findings strengthen the concept that changes in mechanical cues can initiate a pathophysiological process in the glomerulus, not only altering podocyte actin cytoskeleton, but also extending the detrimental effect to the renal progenitor population. This underscores the significance of the cytoskeleton as a druggable target for kidney diseases.

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The Mechanical Contribution of Vimentin to Cellular Stress Generation

Cited by 10 publications

References 35 publications

Vimentin Intermediate Filaments Can Enhance or Abate Active Cellular Forces in a Microenvironmental Stiffness-Dependent Manner

Vimentin Intermediate Filaments Can Enhance or Abate Active Cellular Forces in a Microenvironmental Stiffness-Dependent Manner

Vimentin Diversity in Health and Disease

Modeled microgravity unravels the roles of mechanical forces in renal progenitor cell physiology

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