Self-amplifying Loop of NF-κB and Periostin Initiated by PIEZO1 Accelerates Mechano-induced Senescence of Nucleus Pulposus Cells and Intervertebral Disc Degeneration
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA770632 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Abnormal mechanical load is a main risk factor of intervertebral disc degeneration (IDD), and cellular senescence is a pathological change in IDD. Additionally, extracellular matrix (ECM) stiffness promotes human nucleus pulposus cells (hNPCs) senescence. However, the molecular mechanism underlying mechano-induced cellular senescence and IDD progression is not yet fully elucidated. First, we demonstrated that mechano-stress promoted hNPCs senescence via NF-κB signaling. Subsequently, we identified periostin as the main mechano-responsive molecule in hNPCs through unbiased sequencing, which was transcriptionally upregulated by NF-κB p65; moreover, secreted periostin by senescent hNPCs further promoted senescence and upregulated the catabolic process in hNPCs through activating NF-κB, forming a positive loop. Both Postn (encoding periostin) knockdown via siRNA and periostin inactivation via neutralizing antibodies alleviated IDD and NPCs senescence. Furthermore, we found that mechano-stress initiated the positive feedback of NF-κB and periostin via PIEZO1. PIEZO1 activation by Yoda1 induced severe IDD in rat tails without compression, and Postn knockdown alleviated the Yoda1-induced IDD in vivo. Here, we reported for the first time that self-amplifying loop of NF-κB and periostin initiated via PIEZO1 under mechano-stress accelerated NPCs senescence, leading to IDD. Furthermore, periostin neutralizing antibodies, which may serve as potential therapeutic agents for IDD, interrupted this loop.
2022-06-06 | GSE185728 | GEO
Project description:We compared transcriptional differences between Periostin siRNA treated and GFP-siRNA treated in OP9 cells using Affymetrix mouse 430_2 array.
2012-01-26 | E-MTAB-519 | biostudies-arrayexpress
Project description:Mechanical overload of the vascular wall is a pathological hallmark of life-threatening abdominal aortic aneurysms (AAA). However, how this mechanical stress resonates at the unicellular level of vascular smooth muscle cells (VSMC) is undefined. Here, we combined novel tweezers-based micromechanical system and single-cell RNA sequencing to map defective mechano-phenotype signatures of VSMC in AAA. Notably, theoretical modelling predicted that cytoskeleton alterations fueled cell membrane tension of VSMC, thereby modulating their mechanoallostatic responses which were validated by live micromechanical measurements. Mechanistically, VSMC gradually adopted a mechanically solid-like state by upregulating CSK crosslinker, α-actinin2, in the presence of AAA-promoting signal, Netrin-1, thereby directly powering the activity of mechanosensory ion channel Piezo1. Inhibition of Piezo1 prevented mice from developing AAA by alleviating pathological vascular remodeling. Our findings demonstrate that deviations of mechanosensation behaviors of VSMC is detrimental for AAA and identifies Piezo1 as a novel culprit of mechanically fatigued aorta in AAA.
2021-11-01 | GSE186865 | GEO
Project description:Angiopoietin-Tie1 signaling is required for lymphatic vascular integrity and both ANGPT2 and TIE1 genetic variants have been associated with lymphedema in patients1, 2. Concurrent with growth-factor signaling, mechanical forces sensed by lymphatic endothelial cells (LECs) are also needed to regulate lymphatics3, 4. How these two pathways might interact in the lymphatic system is unknown. Here, we identified a regulatory network in LECs linking activation of the mechanosensory channel, PIEZO1 to Angiopoietin-Tie signaling and repression of a downstream FOXO1 transcriptional response. RNAseq analysis of dermal LECs from Tie1-deficient embryos showed persistent FOXO1 activity with downregulation of LEC-associated genes including Ccl21a, Foxc2, Gata2 and Gja4, as well as increased expression of the mechanosensory channel, Piezo1. Activation of PIEZO1 in human dermal LECs (HDLECs) by the small molecule agonist, Yoda1, triggered exocytosis of the Tie ligand, Angiopoietin-2 (ANGPT2), activation of Tie/AKT/PI3K signaling and export of FOXO1 out of the nucleus. Our data identify a novel molecular pathway linking mechano-transduction to ANGPT2-Tie1 activity and dynamic modulation of FOXO1 activity needed for patterning and function of the lymphatic system
2024-03-05 | GSE211849 | GEO
Project description:In gastric cancer (GC), PIEZO1 was suggested to promote cell migration by interacting with Trefoil factor family 1 (TFF1) and serve as a therapeutic target against invasion and metastasis. In addition, PIEZO1 demonstrates abundant expression in most GC cell lines and primary samples and highly-expressed PIEZO1 is associated with poor disease-specific survival. As Yoda1 is known to be an agonist of PIEZO1, we try to explore the PIEZO1 function in GC by Yoda1 treatment.
2023-12-08 | GSE228691 | GEO
Project description:Synovial and bone marrow mesenchymal stem cells after intradiscally injection show regenerative effects of nucleus pulposus. Microarray analyses of rats were performed to investigate the closeness of the gene profiles between the nucleus pulposus cells and the synovial or bone marrow mesenchymal stem cells. To investigate interaction between synovial mesenchymal stem cells and nucleus pulposus cells, human synovial mesenchymal stem cells and rat nucleus pulposus cells were co-cultured, and species specific microarray were performed. Synovium of knee joints, bone marrow and nucleus pulposus were harvested from rat or human, and cells were isolated for RNA extraction and hybridization on Affymetrix microarrays. To compare the gene profiles each other, isolated cells were mono-cultured respectively, and human synovial mesenchymal stem cells and rat nucleus pulposus cells were co-cultured.
2010-10-11 | E-GEOD-24612 | biostudies-arrayexpress
Project description:Periostin, a matricellular protein, has been reported to be important in supporting tumor cell dissemination. However, the molecular mechanisms underlying periostin function within the tumor microenvironment are poorly understood. In this study, we observe that loss of periostin decreases esophageal squamous cell carcinoma (ESCC) tumor growth in vivo and demonstrate that periostin cooperates with a conformational missense p53 mutation to enhance invasion. Pathway analyses reveal that invasive esophageal cells expressing periostin and p53R175H mutation display activation of signal transducer and activator of transcription 1 (STAT1) target genes, suggesting that the induction of STAT1 and STAT1-related genes could foster a permissive microenvironment that facilitates invasion of esophageal epithelial cells into the extracellular matrix (ECM). Genetic knockdown of STAT1 in transformed esophageal epithelial cells underscores the importance of STAT1 in promoting invasion and potentiate tumor resistance to genotoxic stress. Furthermore, we find that STAT1 is activated in ESCC xenograft tumors but this activation is attenuated with inducible knockdown of periostin in ESCC tumors. Overall, these results highlight the molecular mechanisms supporting the capacity of periostin in mediating tumor invasion during ESCC development. Pre-clinical study hTERT: EPC cells immortalized by expression of hTERT hTERT_p53: EPC cells expressing hTERT and mutant P53 hTERT_p53_POSTN: EPC cells expressing hTERT, mutant P53, and POSTN.
2016-06-01 | E-GEOD-48999 | biostudies-arrayexpress
Project description:Piezo1 is a mechanosensitive ion channel that has gained recognition for its role in regulating diverse physiological processes. However, the influence of Piezo1 in inflammatory disease, including infection and tumor-immunity, is not well-studied. We postulated that Piezo1 links physical forces to immune regulation in myeloid cells. We discovered signal transduction via Piezo1 in myeloid cells and established this channel as the primary sensor of mechanical stress in these cells. Global inhibition of Piezo1 was protective against both cancer and septic shock and resulted in a diminution in suppressive myeloid cells. Moreover, deletion of Piezo1 in myeloid cells protected against cancer and increased survival in poly-microbial sepsis. Mechanistically, we show that mechanical stimulation promotes Piezo1-dependent myeloid cell expansion by suppressing Rb. We further show Piezo1-mediated silencing of Rb is regulated via upregulation of HDAC2. Collectively, our work uncovers Piezo1 as a targetable immune checkpoint that drives immune-suppressive myelopoiesis in cancer and infectious disease.
2020-08-21 | GSE155340 | GEO
Project description:In gastric cancer (GC), PIEZO1 was suggested to promote cell migration by interacting with Trefoil factor family 1 (TFF1) and serve as a therapeutic target against invasion and metastasis. In addition, PIEZO1 demonstrates abundant expression in most GC cell lines and primary samples and highly-expressed PIEZO1 is associated with poor disease-specific survival. Thus, we try to explore the PIEZO1 function in GC by knocking down assay.
2023-12-08 | GSE228690 | GEO
Project description:Idiopathic pulmonary fibrosis (IPF) is a devastating disease with only three to five years of the median survival. Fibroblast proliferation is a hallmark of IPF as well as secretion of extracellular matrix proteins from fibroblasts. However, it is still uncertain how IPF fibroblasts acquire the ability to progressively proliferate. Periostin is a matricellular protein that is highly expressed in the lung tissues of IPF patients and plays a critical role in the pathogenesis of pulmonary fibrosis. However, it remains undetermined whether periostin affects proliferation of lung fibroblasts. In this study, we first comprehensively tried to identify periostin-dependently expressed genes in lung fibroblasts finding that many cell-cycle–related genes are involved in the gene profile. We confirmed that periostin silencing downregulates expression of several cell-cycle–related molecules including the cyclin family, the CDK family, the E2F family, and the transcriptional factors such as B-MYB and FOXM1 in lung fibroblasts. Accordingly, periostin silencing slowed proliferation of lung fibroblasts and affects the distribution of cell cycle particularly at the G1/S checkpoint and drives the cells into G1 arrest. Lung fibroblasts derived from IPF patients also required periostin for maximum proliferation. Moreover, CP4715, a potent inhibitor against integrin V3, a periostin receptor, downregulated proliferation along with expression of cell-cycle–related genes in IPF lung fibroblasts as well as normal lung fibroblasts. These results demonstrate that periostin plays a critical role in proliferation of lung fibroblasts and provide us a beneficial basis to apply the inhibitors against the periostin/integrin V3 interaction to IPF patients.
2020-04-14 | GSE132917 | GEO