Gene expression profiling of Tsp1 deficient rat aortic smooth muscle cells with mechanical stretch
Ontology highlight
ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE131750 | GEO | 2020/03/17
REPOSITORIES: GEO
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Project description:Mammalian cells are surrounded by the extracellular matrix (ECM), which regulates intercellular signal transduction and provides structural support to cells. Mechanical forces generated by ECM play a key role in regulating cell behaviors including survival, growth, mobility, and differentiation. However, it is unclear how mechanical forces are sensed by cells and transmit biochemical signals to cell fate-determining transcription factors such as YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif). Here we show the identification of Ras-associated protein 2 (RAP2) as an intracellular signal transducer that senses ECM rigidity and modulates cell survival and growth by negatively regulating YAP/TAZ. Activation of RAP2 by low ECM stiffness or contact inhibition triggers YAP/TAZ phosphorylation. Deletion of RAP2 leads to sustained YAP/TAZ activation in cells that grow on soft matrix or undergo contact inhibition, alters transcription programs initiated by low matrix stiffness, and results in cell transformation and malignant growth. Mechanistically, RAP2 can directly bind to Mitogen-activated protein kinase kinase kinase kinase 4/6/7 (MAP4K4/6/7) or Rho GTPase activating protein 29 (ARHGAP29), both of which lead to LATS1/2 activation and YAP/TAZ inhibition. These findings define a new molecular pathway that transmits mechanical cues to their effectors in the nucleus.
2018-07-09 | GSE98547 | GEO
Project description:Podocytes are terminally differentiated cells at the kidney filtration barrier and exposed to considerable mechanical strain. Podocyte injury causes morphological changes as a result of cytoskeletal reorganizations and failure of the filtration barrier. The transcriptional co-activators YAP/TAZ are tightly controlled through hippo signaling and responsive to mechanical cues. Here, we show that YAP is upregulated upon podocyte injury to activate YAP-dependent target genes. This activation preceded the development of proteinuria. In contrast, similar perturbations of cells in culture did not reveal increased YAP activity but showed a downregulation of YAP/TAZ activity when cells were grown on stiff surface. However, culture of cells on soft matrix or inhibition of stress fiber formation allowed recapitulation of the damage-induced YAP upregulation indicating a mechanotransduction-dependent mechanism of YAP hyper-activity. Interestingly, increased expression of YAP targets was confirmed in renal biopsies from patients with glomerular disease. Consistently, pharmacological inhibition of YAP/TEAD activity ameliorated glomerular disease in vivo. These data suggest that perturbation of the mechanosensitive hippo signaling pathway may be a therapeutic principle in podocyte disease.
2017-05-02 | PXD003864 | Pride
Project description:Podocytes are terminally differentiated cells at the kidney filtration barrier and exposed to considerable mechanical strain. Podocyte injury causes morphological changes as a result of cytoskeletal reorganizations and failure of the filtration barrier. The transcriptional co-activators YAP/TAZ are tightly controlled through hippo signaling and responsive to mechanical cues. Here, we show that YAP is upregulated upon podocyte injury to activate YAP-dependent target genes. This activation preceded the development of proteinuria. In contrast, similar perturbations of cells in culture did not reveal increased YAP activity but showed a downregulation of YAP/TAZ activity when cells were grown on stiff surface. However, culture of cells on soft matrix or inhibition of stress fiber formation allowed recapitulation of the damage-induced YAP upregulation indicating a mechanotransduction-dependent mechanism of YAP over-activity. Interestingly, increased expression of YAP targets was confirmed in renal biopsies from patients with glomerular disease. Consistently, pharmacological inhibition of YAP/TEAD activity ameliorated glomerular disease in vivo. These data suggest that perturbation of the mechanosensitive hippo signaling pathway may be a therapeutic principle in podocyte disease.
2017-04-19 | PXD003872 | Pride
Project description:The extracellular matrix (ECM) is fundamental to cellular and tissue structural integrity and provides mechanical cues to initiate diverse biological functions1. The quality and quantity of ECM determines tissue stiffness and controls gene expression, cell fate, and cell cycle progression in various cell types. ECM-cell interactions are mediated by focal adhesions (FAs), the main hub for mechanotransduction, connecting ECM, integrins and cytoskeleton. In the blood vessels, an additional layer of mechanical cues derived from pulsatile blood flow and pressure play a pivotal role in homeostasis and disease development. However, how cells sense and integrate different mechanical cues to maintain the blood vessel wall is largely unknown. Vascular ECM is synthesized by SMCs from mid-gestation to early postnatal period and determines the material and mechanical properties of the blood vessels14. Owing to the long half-life of ECM, blood vessels are generally thought to stand life-long mechanical stress without regeneration, particularly in large arteries. However, it is not completely known whether local micro-remodeling system exists for the maintenance of the vessel wall. To search for a potential remodeling factor(s), we performed cyclic stretch experiments (1 Hz; 20% strain) using rat vascular SMCs for 20 hours (h) with or without Brefeldin A (BFA), a protein transporter inhibitor. Conditioned media (CM) were analyzed using quantitative mass spectrometry.
2020-03-18 | PXD013915 | JPOST Repository
Project description:Cells integrate mechanical cues to direct fate specification to maintain tissue function and homeostasis. While disruption of these cues is known to lead to aberrant cell behavior and chronic diseases (e.g. tendinopathies), the underlying mechanisms by which mechanical signals maintain cell function is not well understood. Here, we show using a novel model of tendon de-tensioning that loss of tensile cues in vivo acutely changes nuclear morphology, positioning, and expression of catabolic gene programs. Using paired ATAC/RNAseq, we further identify that a loss of cellular tension rapidly reduces chromatin accessibility in the vicinity of Yap/Taz genomic targets while also increasing expression of genes involved in matrix catabolism. Overexpression of Yap resulted in a reduction of chromatin accessibility at these matrix catabolic genes, and their transcript levels. Concordantly, depletion of Yap/Taz elevated their expression. Finally, we demonstrate that overexpression of Yap not only prevents the induction of a broad catabolic program following a loss of cellular tension, but also preserves the underlying chromatin state from force induced alterations. Taken together, these results provide novel mechanistic details by which mechanical signals regulate tendon cell function to preserve matrix homeostasis through a Yap/Taz axis.
2022-07-14 | GSE207896 | GEO
Project description:The renewing human epidermis constantly senses and adapts to a wide range of mechanical cues that are ubiquitous throughout life. The mechanisms of how mechanical forces are responded by interfollicular epidermal stem cells (IFESCs) and are transmitted directly into nucleus to modify gene expression was discovered to be mediated by transcriptional coactivators YAP. Interestingly, YAP, a critical modulator in controlling organ size by regulating both cell proliferation and apoptosis, was also found to induce self-renewal or amplification of epidermal progenitor/stem cells, and balance epidermal growth and differentiation. Because growth regulation imposed by different stimuli is achieved through distinct YAP target genes even in a single cell type. This study used chromatin immunoprecipitation (ChIP) coupled with human promoter tiling microarray analysis (ChIP-on-chip) to profile YAP at promoters genome-wide. The goal of the study was to identify the target genes occupied by YAP in IFESCs under the mechanical stretch condition.
2018-07-24 | GSE71314 | GEO
Project description:Tissue-scale architecture and mechanical properties instruct cell behavior in physiological and diseased conditions, but our understanding of the underlying mechanisms remains fragmentary. Here we show that ECM stiffness, spatial confinements, and applied forces including stretching of the mouse skin regulate mitochondrial dynamics. Actomyosin tension promotes phosphorylation of MIEF1, limiting the recruitment of DRP1 at mitochondria, peri-mitochondrial F-actin formation, and mitochondrial fission. Strikingly, mitochondrial fission is also a general mechanotransduction mechanism. Indeed we found that DRP1- and MIEF1-dependent fission is required and sufficient to regulate three transcription factors of broad relevance such as YAP-TAZ, SREBP1-2, and NRF2 to control cell proliferation, lipogenesis, antioxidant metabolism, chemotherapy resistance, and adipocyte differentiation in response to mechanical cues. This extends to the mouse liver, where DRP1 regulates hepatocyte proliferation and identity, hallmark YAP-dependent phenotypes. We propose that mitochondria fulfill a unifying signaling function by which the mechanical tissue microenvironment coordinates complementary cell functions.
2024-09-02 | PXD040502 | Pride
Project description:Cells sense the biophysical properties of the surrounding microenvironment. In particular, the stiffness of the extracellular milieu can be interrogated by cells and integrated through mechanotransduction. Many cellular processes (like proliferation, migration, or differentiation) depend on the mechanical status of the cell (being largely dictated by actomyosin-dependent intracellular contractility), which in turn is influenced by the mechanical properties of the microenvironment. In this study, we explored the influence of substrate stiffness on the proteome of undifferentiated human umbilical cord matrix mesenchymal stem/stromal cells (hUCM-MSCs). The relative abundance of several identified proteins suffered significant changes when comparing between substrates. Interestingly, many of such proteins are related to the regulation of the actin cytoskeleton, a main player of mechanotransduction and cell physiology in response to mechanical cues.
2020-07-20 | PXD017674 | Pride
Project description:Fetal bone development occurs by endochondral conversion of avascular cartilage to vascularized bone at the growth plate. This requires coordinated mobilization of osteoblast precursors with blood vessels. In adult bone, vessel-adjacent osteoblast precursors are maintained by mechanical stimuli; however, the mechanisms by which these cells mobilize and respond to mechanical cues during embryonic development are unknown. Here, we unify osteoblast precursor co-mobilization and mechanotransduction in a single signaling pathway, via the mechanosensitive transcriptional regulators YAP and TAZ. We show that YAP and TAZ spatially couple osteoblast precursor mobilization to angiogenesis, regulate vascular loop morphogenesis to control growth plate remodeling, and mediate mechanoregulation of load-induced osteogenesis in embryonic bone. Mechanistically, YAP and TAZ uniquely regulate a subset of osteoblast-lineage cells, identified by single-cell RNA sequencing as vessel-associated osteoblast precursors. Among these cells, YAP and TAZ regulate expression of the angiogenic chemokine, Cxcl12. Functionally, in 3D human cell co-culture, CXCL12 treatment rescued angiogenesis impaired by stromal cell YAP/TAZ depletion. Together, these data establish new functions of the vessel-associated osteoblast precursors in endochondral bone development.
2023-11-15 | GSE227818 | GEO
Project description:RAP2 Mediates Mechanotransduction to Hippo pathway
| PRJNA385490 | ENA