Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA136837 | ENA |
REPOSITORIES: ENA
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Project description:Hypertrophic scar (HTS) formation is characterized by exuberant fibroproliferation for reasons that remain poorly understood1. One important but often overlooked component of wound repair is mechanical force, which regulates reciprocal cell-matrix interactions through focal adhesion components including focal adhesion kinase (FAK)1,2. Here we report that FAK is activated following cutaneous injury and that this activation is potentiated by mechanical loading. Transgenic mice lacking fibroblast-specific FAK exhibit significantly less fibrosis in a preclinical model of HTS formation. Inflammatory pathways involving monocyte chemoattractant protein-1 (MCP-1), a chemokine highly implicated in human skin fibrosis3, are triggered following FAK activation, mechanistically linking physical force to fibrosis. Further, small molecule inhibition of FAK effectively abrogates fibroproliferative mechanisms in human cells and significantly reduces scar formation in vivo. Collectively, these findings establish a molecular basis for HTS formation based on the mechanical activation of fibroblast-specific FAK and demonstrate the therapeutic potential of targeted mechanomodulatory strategies.
2011-01-14 | GSE26390 | GEO
Project description:Hypertrophic scar (HTS) formation is characterized by exuberant fibroproliferation for reasons that remain poorly understood1. One important but often overlooked component of wound repair is mechanical force, which regulates reciprocal cell-matrix interactions through focal adhesion components including focal adhesion kinase (FAK)1,2. Here we report that FAK is activated following cutaneous injury and that this activation is potentiated by mechanical loading. Transgenic mice lacking fibroblast-specific FAK exhibit significantly less fibrosis in a preclinical model of HTS formation. Inflammatory pathways involving monocyte chemoattractant protein-1 (MCP-1), a chemokine highly implicated in human skin fibrosis3, are triggered following FAK activation, mechanistically linking physical force to fibrosis. Further, small molecule inhibition of FAK effectively abrogates fibroproliferative mechanisms in human cells and significantly reduces scar formation in vivo. Collectively, these findings establish a molecular basis for HTS formation based on the mechanical activation of fibroblast-specific FAK and demonstrate the therapeutic potential of targeted mechanomodulatory strategies. Wildtype murine tissue was harvested at either day 6 or 14 post-injury following 48 hours or 10 days of mechanical loading, respectively (n=4 mice per group per time point). Murine RNA was isolated, labeled, and hybridized to the GeneChip microarray according to the manufacturer’s protocols (Affymetrix, Santa Clara, CA, USA). Each gene in the microarray was represented by 20 oligonucleotide pairs, with each pair consisting of an oligonucleotide perfectly matched to the cDNA sequence, and a second oligonucleotide containing a single base mismatch. Raw microarray data (sample intensity files) were processed using GeneSpring GX 11.0 (Agilent Technologies Inc., Santa Clara, CA, USA).
2011-01-14 | E-GEOD-26390 | biostudies-arrayexpress
Project description:The allostatic adaption VSMCs to a mechanical perturbation relies on the interaction of the CSK contractile components to generate cellular force, as well as the engagement of the mechanosensitive signaling elements, i.e. the interplay among mechanosensitive ion channels, integrin-focal adhesion-actin axis, and calcium signal that convert the mechanical input into cellular contractile response We used miroarray to analyze the biophysical mechanisms underlying aging-associated decline in mechanosensation and VSMC functions
2023-11-01 | GSE243736 | GEO
Project description:Mechanical force has been shown to regulate periodontal ligament cells (PDLs) behaviors. However, different force types lead to distinct PDLs’ responses. Here, the differential gene expression profiling of PDLs subjected to static and intermittent compressive forces was examined using RNA sequencing technique. Results demonstrated that the static and intermittent compressive force treated PDLs exhibited the differential regulation genes. KEGG pathway enrichment analysis revealed that focal adhesion and transforming growth factor beta signaling pathway were commonly upregulated while calcium signaling pathway was downregulated in both static and intermittent compressive force-treated PDLs. Interestingly, Wnt signaling pathway was upregulated only in the PDLs that subjected to the intermittent compressive force.
2019-07-23 | GSE112122 | GEO
Project description:Purpose: mechanical homeostasis is a crucial process for Humen dermal fibroblast cell (HDFs) survival and functionality. Cell can sense environmental change and modify the expression of extracellular matrix, focal adhesion and cytoskeleton protein to maintain the correct mechanical homeostasis. In this study we observed change in microRNA levels linked with mechanical response. HDFs were seeded for 48 our on PDMS 3 kPa and 30 kPa substrate coating with fibronectin to simulate "soft" and "stiff" substrate, then sRNA-seq was performed.
2019-03-31 | GSE123008 | GEO
Project description:Cell adhesion to the extracellular matrix occurs through integrin-mediated focal adhesions, which sense the mechanical properties of the substrate and impact cellular functions such as cell migration. Mechanotransduction at focal adhesions affects the actomyosin network and contributes to cell migration. Despite being key players in cell adhesion and migration, the role of microtubules in mechanotransduction has been overlooked. Here, we show that substrate rigidity increases microtubule acetylation through β1 integrin signalling in primary rat astrocytes. Moreover, αTAT1, the enzyme responsible for microtubule acetylation, interacts with a major mechanosensing focal adhesion protein, Talin, and is able to tune the distribution of focal adhesions depending on the matrix rigidity. αTAT1 also reorganises the actomyosin network, increases traction force generation and cell migration speed on stiff substrates. Mechanistically, acetylation of microtubules promotes the release of microtubule-associated RhoGEF, GEF-H1 into the cytoplasm, which then leads to RhoA activation and high actomyosin contractility. Thus, we propose a novel feedback loop involving a crosstalk between microtubules and actin in mechanotransduction at focal adhesions whereby, cells sense the rigidity of the substrate through integrin-mediated adhesions, modulate their levels of microtubule acetylation, which then controls the actomyosin cytoskeleton and force transmission on the substrate to promote mechanosensitive cell migration.
2021-11-02 | PXD015871 | Pride
Project description:Mechanical stress is a potent regulator of cell growth, contractility and gene regulation. Abnormal uterine distension during pregnancy increases the risk of preterm birth and likely activates crosstalk between multiple signaling networks with protein phosphorylation playing a critical role. Telomerized human uterine smooth muscle cells were exposed to 18% biaxial stretch for 5 min and the phosphoproteome was probed by mass spectrometry. We observed specific phospho-activation of mitogen activated protein kinase at threonine 183 and tyrosine 185, myosin regulatory light chain 9 at threonine 19, and heat shock protein 27 at serine 82. Our analysis revealed protein phosphorylation changes in signaling pathways related to actin cytoskeleton remodeling, activation of the focal adhesion kinase pathway, smooth muscle contraction and mechanistic target of rapamycin activation. These data point to potential mechanistic links between stretch-induced phosphorylation and development of the contractile phenotype in myometrial cells.
2019-04-10 | PXD002538 | Pride
Project description:Endothelin-1 (ET-1) plays a critical role in connective tissue remodeling by fibroblasts during tissue repair and fibrosis. We investigated the molecular pathways in the transmission of ET-1 signals that lead to features of connective tissue remodeling, in particular the role of FAK (focal adhesion kinase). We used microarrays to investigated whether FAK is required for ET-1 to promote the global programme of gene expression underlying myofibroblast formation and identified distinct classes of up-regulated genes during this process. Genes whose induction by ET-1 required FAK Affymetrix Mouse Genome 430 2.0 GeneChips were used to identify differential gene expression changes bewteen samples.
2012-06-30 | E-GEOD-30356 | biostudies-arrayexpress