In wound repair vimentin mediates the transition of mesenchymal leader cells to a myofibroblast phenotype

Walker, James B.; Bleaken, Brigid M.; Romisher, Alison; Alnwibit, Alhanoof A; Menko, A. Sue

doi:10.1091/mbc.e17-06-0364

Cited by 70 publications

(109 citation statements)

References 81 publications

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“…31,36 Vimentin is not only up-regulated in the cells but also excreted into the extracellular space. 37 The result of our studies suggest that the mechanical changes vimentin undergoes in this pH range are considerable and might play a role within cells as well as the extracellular space during skin repair. Intracellular and extracellular pH gradients have furthermore been found to be a feature of migrating tumor cells.…”

Section: If Stiffening Saturates At Low Phmentioning

confidence: 73%

Tuning Intermediate Filament Mechanics by Variation of pH and Ion Charges

Schepers

Lorenz

Köster

2019

Preprint

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8The cytoskeleton is formed by three types of filamentous proteins -microtubules, actin fila-9 ments, and intermediate filaments (IFs) -and enables cells to withstand external and internal 10 forces. Vimentin is the most abundant IF in humans and has remarkable mechanical properties, 11 such as high extensibility and stability. It is, however, unclear to which extent these properties 12 are influenced by the electrostatic environment. Here, we study the mechanical properties of 13 single vimentin filaments by employing optical trapping combined with microfluidics. Force-14 strain curves, recorded at varying ion concentrations and pH values, reveal that the mechanical 15 properties of single vimentin IFs are influenced by direct (pH) and indirect (ionic) charge vari-16 ations. By combination with Monte Carlo simulations, we connect these altered mechanics to 17 electrostatic interactions of subunits within the filaments. We thus find possible mechanisms 18 that allow cells to locally tune their stiffness without remodelling the entire cytoskeleton. 19One-Sentence-Summary: Adaptable force-strain behaviour of single cytoskeletal filaments 20 in varying electostatic conditions allow cells to tune their mechanical properties rapidly and 21 locally. 22 1 MAIN TEXT 23 Introduction 24It is meanwhile well accepted that the mechanical properties of cells are, to a large extent, 25 governed by the cytoskeleton, a stabilising, yet flexible framework, which is composed of mi-26 crotubules, actin filaments, and intermediate filaments (IFs), together with motor proteins and 27 crosslinkers. While microtubules and actin filaments are conserved in eukaryotic cell types, 28 there are around 70 different genes encoding IFs in man that are expressed according to the 29 cell's specific requirements (1, 2). 30Despite differences in their amino acid sequence, all cytoskeletal IF proteins share their sec-31 ondary structure with a tripartite alpha-helical rod and disordered head and tail domains (3, 4). 32During the hierarchical assembly, two monomers form a parallel coiled coil and these dimers 33 organise into anti-parallel tetramers in a half-staggered arrangement. The tetramers assemble 34 laterally to form unit length filaments (ULFs), which in turn elongate to filaments by end-to-end 35 annealing (3). The resulting biopolymer comprises a complex high-order arrangement of coiled 36 coils (3), which allows IFs to be extended up to at least 4.5-fold their initial length (5-7). This 37 enormous extensibility is in stark contrast to microtubules and F-actin (8). 38Vimentin is the IF typically expressed in mesenchymal cells (2) and up-regulated during the 39 epithelial-to-mesenchymal transition in wound healing, early embryogenesis, and cancer meta-40 stasis (9). In addition to being highly extensible (7, 10, 11) vimentin is flexible (12-14) and 41 stable (15). During stretching, three regimes are observed in the force-strain data (7, 10, 11, 16, 42 17): an initial linear, elastic increase, a plateau of relatively constant force...

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Section: If Stiffening Saturates At Low Phmentioning

confidence: 73%

Tuning Intermediate Filament Mechanics by Variation of pH and Ion Charges

Schepers

Lorenz

Köster

2019

Preprint

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“…Due to the numerous roles of vimentin, the effect of vimentin inhibition in non-malignant cells should be considered. To this end, consequences of its inhibition should be studied in animal models and effects on processes entailing cell migration (such as wound healing [73,133] or immune response [87,134]) should be carefully examined. However, since mice lacking vimentin develop and reproduce without any major problem [135], we can anticipate that beneficial vimentin inhibition in malignant cells outweighs any potential adverse effects.…”

Section: Discussionmentioning

confidence: 99%

Vimentin Intermediate Filaments as Potential Target for Cancer Treatment

Strouhalova

Přechová

Gandalovičová

et al. 2020

Cancers

189

143

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Intermediate filaments constitute the third component of the cellular skeleton. Unlike actin and microtubule cytoskeletons, the intermediate filaments are composed of a wide variety of structurally related proteins showing distinct expression patterns in tissues and cell types. Changes in the expression patterns of intermediate filaments are often associated with cancer progression; in particular with phenotypes leading to increased cellular migration and invasion. In this review we will describe the role of vimentin intermediate filaments in cancer cell migration, cell adhesion structures, and metastasis formation. The potential for targeting vimentin in cancer treatment and the development of drugs targeting vimentin will be reviewed.

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“…Vimentin is an essential element of inflammation and fibrosis. Walker et al 40 showed that vimentin mediates the transition of mesenchymal leader cells to a myofibroblast phenotype, facilitating fibrosis in wound repair, while vimentin deficiency resulted in a blunted inflammatory response. Vimentin is also a key regulator of the NLRP3 inflammasome, promoting lung inflammation and fibrosis 13 .…”

Section: Discussionmentioning

confidence: 99%

A novel antifibrotic strategy utilizing conditioned media obtained from miR-150-transfected adipose-derived stem cells: validation of an animal model of liver fibrosis

et al. 2020

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The limitations of stem cells have led researchers to investigate the secretome, which is the secretory materials in stem cells, since the principal mechanism of action of stem cells is mediated by the secretome. In this study, we determined the antifibrotic potential of the secretome released from miR-150-transfected adipose-derived stromal cells (ASCs). The secretome released from ASCs that were transfected with antifibrotic miR-150 was obtained (referred to as the miR-150 secretome). To validate the antifibrotic effects of the miR-150 secretome, we generated in vitro and in vivo models of liver fibrosis by treating human hepatic stellate cells (LX2 cells) with thioacetamide (TAA) and subcutaneous injection of TAA into mice, respectively. In the in vitro model, more significant reductions in the expression of fibrosisrelated markers, such as TGFβ, Col1A1, and α-SMA, were observed by using the miR-150 secretome than the control secretome, specifically in TAA-treated LX2 cells. In the in vivo model, infusion of the miR-150 secretome into mice with liver fibrosis abrogated the increase in serum levels of systemic inflammatory cytokines, such as IL-6 and TNF-α, and induced increased expression of antifibrotic, proliferation, and antioxidant activity markers in the liver. Our in vitro and in vivo experiments indicate that the miR-150 secretome is superior to the naive secretome in terms of ameliorating liver fibrosis, minimizing systemic inflammatory responses, and promoting antioxidant enzyme expression. Therefore, we conclude that miR-150 transfection into ASCs has the potential to induce the release of secretory materials with enhanced antifibrotic, proliferative, and antioxidant properties.

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In wound repair vimentin mediates the transition of mesenchymal leader cells to a myofibroblast phenotype

Cited by 70 publications

References 81 publications

Tuning Intermediate Filament Mechanics by Variation of pH and Ion Charges

Tuning Intermediate Filament Mechanics by Variation of pH and Ion Charges

Vimentin Intermediate Filaments as Potential Target for Cancer Treatment

A novel antifibrotic strategy utilizing conditioned media obtained from miR-150-transfected adipose-derived stem cells: validation of an animal model of liver fibrosis

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