Browse
Submit Data
Databases
API
Help

Dataset Information

27 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Mechanical Forces Regulate Asymmetric Vascular Cell Alignment.

ABSTRACT: Mechanical forces between cells and their microenvironment critically regulate the asymmetric morphogenesis and physiological functions in vascular systems. Here, we investigated the asymmetric cell alignment and cellular forces simultaneously in micropatterned endothelial cell ring-shaped sheets and studied how the traction and intercellular forces are involved in the asymmetric vascular morphogenesis. Tuning the traction and intercellular forces using different topographic geometries of symmetric and asymmetric ring-shaped patterns regulated the vascular asymmetric morphogenesis in vitro. Moreover, pharmacologically suppressing the cell traction force and intercellular force disturbed the force-dependent asymmetric cell alignment. We further studied this phenomenon by modeling the vascular sheets with a mechanical force-propelled active particle model and confirmed that mechanical forces synergistically drive the asymmetric endothelial cell alignments in different tissue geometries. Further study using mouse diabetic aortic endothelial cells indicated that diseased endothelial cells exhibited abnormal cell alignments, traction, and intercellular forces, indicating the importance of mechanical forces in physiological vascular morphogenesis and functions. Overall, we have established a controllable micromechanical platform to study the force-dependent vascular asymmetric morphogenesis and thus provide a direct link between single-cell mechanical processes and collective behaviors in a multicellular environment.

SUBMITTER: Cui X

PROVIDER: S-EPMC7677134 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Myosin IIA-mediated forces regulate multicellular integrity during vascular sprouting.

Project description:Angiogenic sprouting is a critical process involved in vascular network formation within tissues. During sprouting, tip cells and ensuing stalk cells migrate collectively into the extracellular matrix while preserving cell-cell junctions, forming patent structures that support blood flow. Although several signaling pathways have been identified as controlling sprouting, it remains unclear to what extent this process is mechanoregulated. To address this question, we investigated the role of cellular contractility in sprout morphogenesis, using a biomimetic model of angiogenesis. Three-dimensional maps of mechanical deformations generated by sprouts revealed that mainly leader cells, not stalk cells, exert contractile forces on the surrounding matrix. Surprisingly, inhibiting cellular contractility with blebbistatin did not affect the extent of cellular invasion but resulted in cell-cell dissociation primarily between tip and stalk cells. Closer examination of cell-cell junctions revealed that blebbistatin impaired adherens-junction organization, particularly between tip and stalk cells. Using CRISPR/Cas9-mediated gene editing, we further identified NMIIA as the major isoform responsible for regulating multicellularity and cell contractility during sprouting. Together, these studies reveal a critical role for NMIIA-mediated contractile forces in maintaining multicellularity during sprouting and highlight the central role of forces in regulating cell-cell adhesions during collective motility.

| S-EPMC6727772 | biostudies-literature

Mechanical forces regulate cardiomyocyte myofilament maturation via the VCL-SSH1-CFL axis

Project description:Mechanical forces regulate cell behavior and tissue morphogenesis. In particular, cardiac tissues require mechanical stimuli generated by the heartbeat for differentiation and maturation, but the molecular mechanisms underlying these processes remain unclear. Here, we first show that mechanical forces acting via the mechanosensitive factor Vinculin (VCL) are essential for cardiomyocyte myofilament maturation and that cardiac contractility regulates the localization and activation of Vinculin. To further analyze the role of Vinculin in myofilament maturation, we examined its interactome in contracting cardiomyocytes and found many cytoskeletal factors including actinins. We also identified Slingshot protein phosphatase 1 (SSH1), which we show is recruited by Vinculin to regulate F-actin rearrangement and myofilament maturation through its association with the actin depolymerizing factor Cofilin (CFL). Together, our results reveal that mechanical forces generated by cardiac contractility regulate cardiomyocyte maturation through the VCL-SSH1-CFL axis, providing mechanistic insight into how mechanical forces are transmitted intracellularly to regulate myofilament maturation.

2019-09-06 | PXD014624 | Pride

Mechanical forces regulate elastase activity and binding site availability in lung elastin.

Project description:Many fundamental cellular and extracellular processes in the body are mediated by enzymes. At the single molecule level, enzyme activity is influenced by mechanical forces. However, the effects of mechanical forces on the kinetics of enzymatic reactions in complex tissues with intact extracellular matrix (ECM) have not been identified. Here we report that physiologically relevant macroscopic mechanical forces modify enzyme activity at the molecular level in the ECM of the lung parenchyma. Porcine pancreatic elastase (PPE), which binds to and digests elastin, was fluorescently conjugated (f-PPE) and fluorescent recovery after photobleach was used to evaluate the binding kinetics of f-PPE in the alveolar walls of normal mouse lungs. Fluorescent recovery after photobleach indicated that the dissociation rate constant (k(off)) for f-PPE was significantly larger in stretched than in relaxed alveolar walls with a linear relation between k(off) and macroscopic strain. Using a network model of the parenchyma, a linear relation was also found between k(off) and microscopic strain on elastin fibers. Further, the binding pattern of f-PPE suggested that binding sites on elastin unfold with strain. The increased overall reaction rate also resulted in stronger structural breakdown at the level of alveolar walls, as well as accelerated decay of stiffness and decreased failure stress of the ECM at the macroscopic scale. These results suggest an important role for the coupling between mechanical forces and enzyme activity in ECM breakdown and remodeling in development, and during diseases such as pulmonary emphysema or vascular aneurysm. Our findings may also have broader implications because in vivo, enzyme activity in nearly all cellular and extracellular processes takes place in the presence of mechanical forces.

| S-EPMC2965944 | biostudies-literature

Mechanical forces regulate the interactions of fibronectin and collagen I in extracellular matrix.

Project description:Despite the crucial role of extracellular matrix (ECM) in directing cell fate in healthy and diseased tissues--particularly in development, wound healing, tissue regeneration and cancer--the mechanisms that direct the assembly and regulate hierarchical architectures of ECM are poorly understood. Collagen I matrix assembly in vivo requires active fibronectin (Fn) fibrillogenesis by cells. Here we exploit Fn-FRET probes as mechanical strain sensors and demonstrate that collagen I fibres preferentially co-localize with more-relaxed Fn fibrils in the ECM of fibroblasts in cell culture. Fibre stretch-assay studies reveal that collagen I's Fn-binding domain is responsible for the mechano-regulated interaction. Furthermore, we show that Fn-collagen interactions are reciprocal: relaxed Fn fibrils act as multivalent templates for collagen assembly, but once assembled, collagen fibres shield Fn fibres from being stretched by cellular traction forces. Thus, in addition to the well-recognized, force-regulated, cell-matrix interactions, forces also tune the interactions between different structural ECM components.

| S-EPMC4539566 | biostudies-literature

Mechanical forces regulate the reactivity of a thioester bond in a bacterial adhesin.

Project description:Bacteria must withstand large mechanical shear forces when adhering to and colonizing hosts. Recent structural studies on a class of Gram-positive bacterial adhesins have revealed an intramolecular Cys-Gln thioester bond that can react with surface-associated ligands to covalently anchor to host surfaces. Two other examples of such internal thioester bonds occur in certain anti-proteases and in the immune complement system, both of which react with the ligand only after the thioester bond is exposed by a proteolytic cleavage. We hypothesized that mechanical forces in bacterial adhesion could regulate thioester reactivity to ligand analogously to such proteolytic gating. Studying the pilus tip adhesin Spy0125 of Streptococcus pyogenes, we developed a single molecule assay to unambiguously resolve the state of the thioester bond. We found that when Spy0125 was in a folded state, its thioester bond could be cleaved with the small-molecule nucleophiles methylamine and histamine, but when Spy0125 was mechanically unfolded and subjected to forces of 50-350 piconewtons, thioester cleavage was no longer observed. For folded Spy0125 without mechanical force exposure, thioester cleavage was in equilibrium with spontaneous thioester reformation, which occurred with a half-life of several minutes. Functionally, this equilibrium reactivity allows thioester-containing adhesins to sample potential substrates without irreversible cleavage and inactivation. We propose that such reversible thioester reactivity would circumvent potential soluble inhibitors, such as histamine released at sites of inflammation, and allow the bacterial adhesin to selectively associate with surface-bound ligands.

| S-EPMC5448130 | biostudies-literature

How Biophysical Forces Regulate Human B Cell Lymphomas.

Project description:The role of microenvironment-mediated biophysical forces in human lymphomas remains elusive. Diffuse large B cell lymphomas (DLBCLs) are heterogeneous tumors, which originate from highly proliferative germinal center B cells. These tumors, their associated neo-vessels, and lymphatics presumably expose cells to particular fluid flow and survival signals. Here, we show that fluid flow enhances proliferation and modulates response of DLBCLs to specific therapeutic agents. Fluid flow upregulates surface expression of B cell receptors (BCRs) and integrin receptors in subsets of ABC-DLBCLs with either CD79A/B mutations or WT BCRs, similar to what is observed with xenografted human tumors in mice. Fluid flow differentially upregulates signaling targets, such as SYK and p70S6K, in ABC-DLBCLs. By selective knockdown of CD79B and inhibition of signaling targets, we provide mechanistic insights into how fluid flow mechanomodulates BCRs and integrins in ABC-DLBCLs. These findings redefine microenvironment factors that regulate lymphoma-drug interactions and will be critical for testing targeted therapies.

| S-EPMC5965297 | biostudies-literature

Effect of mechanical constriction forces on breast cell lines transcripts

Project description:During metastatic dissemination, circulating tumour cells (CTCs) enter capillary beds, where they experience mechanical constriction forces. A high-throughput microfluidic platform mimicking human capillaries to investigate the impact of mechanical constriction forces on malignant and normal breast cell lines was developed. Cells were collected after transiting the constrictions, followed by RNA extraction and sequencing. The non-malignant cell line experienced transcriptional changes, particularly downregulation of epithelial markers, while the metastatic cell lines showed minimal alterations.

2024-02-16 | GSE246824 | GEO

Mechanical Forces as Determinants of Disseminated Metastatic Cell Fate.

Project description:Disseminated metastatic cancer cells represent one of the most relevant causes of disease relapse and associated death for cancer patients, and a therapeutic target of the highest priority. Still, our understanding of how disseminated cancer cells survive in the foreign metastatic environment, and eventually cause metastatic outgrowth, remains rather limited. In this review we focus on the cell microenvironment as a key regulator of cell behavior at the metastatic site, and especially on the mechanical properties of the extracellular matrix and associated integrin signaling. We discuss available evidence pointing to a pervasive role of extracellular matrix (ECM) mechanical properties in regulating cancer cell proliferation and survival after dissemination, and propose that this might represent an important bottleneck for cells invading and establishing into a novel tissue. We point to the known molecular players, how these might contribute to modulate the mechanical properties of the metastatic environment, and the response of cells to these cues. Finally, we propose that emerging knowledge on the physical interaction of disseminated metastatic cells and on the downstream mechanotransduction pathways, including YAP/TAZ (Yes-associated protein-1 and WW-domain transcription activator 1) and MRTFs (Myocardin-related transcription factors), may help to identify novel approaches for therapy.

| S-EPMC7016729 | biostudies-literature

Quantifying cell-generated mechanical forces within living embryonic tissues.

Project description:Cell-generated mechanical forces play a critical role during tissue morphogenesis and organ formation in the embryo. Little is known about how these forces shape embryonic organs, mainly because it has not been possible to measure cellular forces within developing three-dimensional (3D) tissues in vivo. We present a method to quantify cell-generated mechanical stresses exerted locally within living embryonic tissues, using fluorescent, cell-sized oil microdroplets with defined mechanical properties and coated with adhesion receptor ligands. After a droplet is introduced between cells in a tissue, local stresses are determined from droplet shape deformations, measured using fluorescence microscopy and computerized image analysis. Using this method, we quantified the anisotropic stresses generated by mammary epithelial cells cultured within 3D aggregates, and we confirmed that these stresses (3.4 nN ?m(-2)) are dependent on myosin II activity and are more than twofold larger than stresses generated by cells of embryonic tooth mesenchyme, either within cultured aggregates or in developing whole mouse mandibles.

| S-EPMC3939080 | biostudies-literature

Are Tumor Cell Lineages Solely Shaped by Mechanical Forces?

Project description:This paper investigates cell proliferation dynamics in small tumor cell aggregates using an individual-based model (IBM). The simulation model is designed to study the morphology of the cell population and of the cell lineages as well as the impact of the orientation of the division plane on this morphology. Our IBM model is based on the hypothesis that cells are incompressible objects that grow in size and divide once a threshold size is reached, and that newly born cell adhere to the existing cell cluster. We performed comparisons between the simulation model and experimental data by using several statistical indicators. The results suggest that the emergence of particular morphologies can be explained by simple mechanical interactions.

| S-EPMC5597711 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data