RNA-seq of wildtype and PIEZO1 knockout mice livers to investigate lipid and glucose regulation by the endothelial force sensor PIEZO1
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Illumina NovaSeq 6000
ORGANISM(S): Mus musculus
SUBMITTER: Chew Weng Cheng
PROVIDER: E-MTAB-9996 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:The mechanisms by which physical forces regulate cells to determine complexities of vascular structure and function are enigmatic. Here we show the role the ion channel subunit Piezo1 (FAM38A). Disruption of mouse Piezo1 gene disturbed vascular development and was embryonic lethal within days of the heart beating to cause blood flow. Importance of Piezo channels as sensors of blood flow was indicated by Piezo1 dependence of shear stress-evoked ionic current and calcium influx in endothelial cells and the ability of exogenous Piezo1 to confer shear stress sensitivity on cells that otherwise lacked. Downstream of this calcium influx was proteoase activity and spatial organization of endothelial cells to the polarity of the applied force. Without Piezo1, normal endothelial cell organization was lacking. The data suggest Piezo1 channels as pivotal integrators of vascular architacture with physiological mechanical force.
2014-08-08 | PXD001099 | Pride
Project description:Healthy alveolar bone is the cornerstone for oral function and oral treatment. In the aging population, increasingly postmenopausal women requiring dental services experiences alveolar bone loss due to estrogen deficiency. Both local factors (occlusal force lose) and systemic factors (estrogen deficiency) affects their alveolar bone health, but the association remains to be clarified. Here, we identified that occlusal force is critical in maintaining alveolar bone mass and PIEZO1 coordinates mechanical force and estrogen, thus orchestrating alveolar bone homeostasis. Mechanistically, both occlusal force loss and PIEZO1 deletion may impair the osteogenesis of alveolar bone and sequentially regulate catabolic metabolism through Fas ligand (FasL)-induced osteoclastic apoptosis. PIEZO1 may promote the activity of signal transducer and activator of transcription 3 (STAT3) and estrogen receptor 1 (ESR1), which cooperatively increase Fasl transcription. This study thus revealed a cooperation between occlusal force and estrogen in maintaining alveolar bone homeostasis through a PIEZO1-STAT3/ESR1-FasL pathway. Our work supports restoration of occlusal force with dental therapies early and suggests that preventing alveolar bone loss is the major priority. PIEZO1 may serve not only as a treatment target for occlusal force loss-induced alveolar bone loss but also as a potential target for metabolic bone loss, especially in older patients.
2025-12-31 | GSE205377 | GEO
Project description:The corneal endothelium plays a primary role in maintaining corneal homeostasis and clarity, and must be surgically replaced with allogenic donor corneal endothelium in the event of visually significant dysfunction. However, a worldwide shortage of donor corneal tissue has led to a search for alternative sources of transplantable tissue. Cultured human corneal endothelial cells (HCEnC) have been shown to restore corneal clarity in experimental models of corneal endothelial dysfunction in animal models, but characterization of cultured HCEnC remains incomplete. To this end, we utilized next-generation RNA sequencing technology to compare the transcriptomic profile of ex vivo human corneal endothelium (evHCEnC) with that of primary HCEnC and HCEnC lines, and to determine the utility of cultured and immortalized corneal endothelial cells as models of in vivo corneal endothelium. Multidimensional analyses of the transcriptome datasets demonstrated that primary HCEnC have a closer relationship to evHCEnC than do immortalized HCEnC. Subsequent analyses showed that the majority of the genes specifically expressed in HCEnC (not expressed in ex vivo corneal epithelium or fibroblasts) demonstrated a marked variability of expression in cultured cells compared with evHCEnC. In addition, genes associated with either corneal endothelial cell function or corneal endothelial dystrophies were investigated. Significant differences in gene expression and protein levels were observed in the cultured cells compared with evHCEnC for each of the genes tested except for AGBL1 and LOXHD1, which were not detected by RNA-seq or qPCR. Our transcriptomic analysis suggests that at a molecular level primary HCEnC most closely resemble evHCEC and thus represent a viable therapeutic option for managing corneal endothelial dysfunction. Our findings also suggest that investigators should perform an assessment of the entire transcriptome of cultured HCEnC prior to determination of the potential clinical utility of the cultured HCEnC for the management of corneal endothelial cell failure. Transcriptomes from ex vivo corneal endothelium, primary cultures and three cell lines were compared. Three samples of each endothelial cell group were submitted for RNA sequencing for a total of 15 samples. The transcriptome for the ex vivo corneal endothelium was used as the reference (i.e., proxy for in vivo corneal endothelium). Transcript abundances for a subset of genes associated with corneal endothelial cell function or disease were validated with qPCR and western blot. Samples of ex vivo endothelium used for validation were independent replicates not used for RNA-sequencing.
2015-09-04 | E-GEOD-65991 | biostudies-arrayexpress
Project description:RNA-seq of wildtype and PIEZO1 knockout mice livers to investigate lipid and glucose regulation by the endothelial force sensor PIEZO1
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Project description:The gut microbiota affects remote organ functions but its impact on organotypic endothelial cell (EC) transcriptomes remains unexplored. The liver endothelium encounters microbiota-derived signals and metabolites via the portal circulation. To pinpoint how gut commensals affect the hepatic sinusoidal endothelium, a magnetic cell sorting protocol, combined with fluorescence activated cell sorting, was used to analyze the transcriptome of hepatic sinusoidal ECs from germ-free (GF) and conventionally-raised (CONV-R) mice by RNA-sequencing. This resulted in a comprehensive map of microbiota-regulated hepatic EC-specific transcriptome profiles. Gene Ontology analysis revealed that several functional processes in the hepatic endothelium were influenced. The absence of a microbiota influenced the expression of genes involved in cholesterol flux and angiogenesis. Specifically, genes functioning in hepatic endothelial sphingosine matabolism and the sphingosine-1-phosphate pathway showed a drastically increased expression in the GF state. Our analyses reveal a prominent role for the microbiota in shaping the transcriptional landscape of the hepatic endothelium.
2021-07-23 | GSE180520 | GEO
Project description:Synovial resident macrophages in humans play a key role in maintaining tissue and synovial fluid homeostasis and typically exhibit protective phenotypes. However, at the start of rheumatoid arthritis, macrophages can adopt inflammation-permissive phenotypes. The factors that influence macrophage phenotype during the early stages of arthritis are not yet fully understood. Interestingly, in mice, mechanical stress is required for the localization of joint inflammation. Given the critical roles of macrophages, we investigated whether mechanosensation contributes to the regulation of macrophage phenotypes. PIEZO1, a well-established mechanosensor expressed on macrophages, regulates various macrophage functions, including migration and phagocytosis. We found that PIEZO1 activation in macrophages shifted their phenotype to a tissue-resident (MERTKhigh, CD36high), inflammation-permissive phenocopy (TREM2low, VSIG4low), with elevated MHC class II and cytokine secretion. Additionally, in vivo activation of PIEZO1 in mice produced similar effects in synovial tissue macrophages (STMs) and led to increased recruitment of monocytes and neutrophils. By dissecting the PIEZO1 signalling pathway, we were able to restore the protective macrophage phenotype by inhibiting calpain signalling and knocking-out HIF1α, both downstream mediators of PIEZO1 activation. Furthermore, we observed that PIEZO1 expression is present in synovial macrophages from patients with active rheumatoid arthritis and decreases during remission, suggesting a link between macrophage PIEZO1 expression and disease activity
2026-01-31 | E-MTAB-15200 | biostudies-arrayexpress
Project description:Background: Hereditary hemorrhagic telangiectasia (HHT) is an inherited vascular disorder characterized by arteriovenous malformations (AVMs). Loss-of-function mutations in Activin receptor-like kinase 1 (ALK1) cause type 2 HHT and Alk1 knockout (KO) mice develop AVMs along with overactivation of VEGFR2/PI3K/AKT signaling. The full spectrum of signaling alterations resulting from ALK1 mutations remains unknown, and more effective and specific inhibitors to combat AVM formation in patients are needed. Methods: Single-cell RNA sequencing of endothelial-specific Alk1 KO mouse retinas and controls was performed. Overexpression of fluid shear stress signaling signatures including the mechanosensitive ion channel PIEZO1 was confirmed in mouse and human HHT2 lesions. Genetic and pharmacological PIEZO1 inhibition was tested in Alk1 KO mice, along with downstream PIEZO1 signaling. Results: A cluster of Alk1 mutant endothelial cells with altered arterio-venous identity overexpressed pathways related to fluid shear stress, hypoxia, inflammation, cell cycle and VEGFR2/PI3K/AKT signaling. Piezo1 deletion and pharmacological inhibition in Alk1-deficient mice mitigated AVM formation, whereas Piezo1 overexpression enhanced AVM formation induced by ALK1 ligand blockade. Mechanistically, PIEZO1 inhibition reduced elevated VEGFR2/AKT, ERK5-p62-KLF4, eNOS, hypoxia, proliferation and inflammation in ALK1 deficient endothelium. Conclusions: PIEZO1 expression and signaling are elevated in HHT2. PIEZO1 blockade reduces AVM formation and alleviates cellular and molecular hallmarks of ALK1-deficient cells. This finding provides new insights into the mechanistic underpinnings of ALK1-related vascular diseases and identifies potential therapeutic targets to prevent AVMs.
2025-07-18 | GSE298122 | GEO
Project description:The mechanosensitive ion channel PIEZO1 has emerged as a key regulator of vascular and skeletal biology. Here, we show that systemic activation of PIEZO1 using the chemical agonist Yoda1 in 3-week-old mice disrupts bone homeostasis by impairing type H endothelial cells and inhibiting osteogenic differentiation. In vivo, Yoda1 treatment significantly reduced the abundance of CD31hiEMCNhi type H vessels and altered trabecular bone microarchitecture without affecting total bone mass. In vitro, Yoda1 inhibited osteogenic gene expression and alkaline phosphatase activity in MC3T3-E1 preosteoblasts. Transcriptomic analysis of Yoda1-treated human bone microvascular endothelial cells (hBMECs) revealed a shift from an angiogenic H-type to a quiescent L-type, accompanied by upregulation of BMP signaling antagonists, particularly GREM1. Functional assays confirmed that GREM1 secreted from Yoda1-stimulated endothelial cells suppresses BMP4-induced osteoblast differentiation via paracrine signaling. Together, these findings uncover a novel endothelial-to-osteoblast regulatory axis mediated by PIEZO1-GREM1-BMP4 signaling, and underscore the context-dependent effects of PIEZO1 activation on bone regeneration.
2026-06-26 | GSE300884 | GEO
Project description:The mechanosensitive ion channel PIEZO1 has emerged as a key regulator of vascular and skeletal biology. Here, we show that systemic activation of PIEZO1 using the chemical agonist Yoda1 in 3-week-old mice disrupts bone homeostasis by impairing type H endothelial cells and inhibiting osteogenic differentiation. In vivo, Yoda1 treatment significantly reduced the abundance of CD31hiEMCNhi type H vessels and altered trabecular bone microarchitecture without affecting total bone mass. In vitro, Yoda1 inhibited osteogenic gene expression and alkaline phosphatase activity in MC3T3-E1 preosteoblasts. Transcriptomic analysis of Yoda1-treated human bone microvascular endothelial cells (hBMECs) revealed a shift from an angiogenic H-type to a quiescent L-type, accompanied by upregulation of BMP signaling antagonists, particularly GREM1. Functional assays confirmed that GREM1 secreted from Yoda1-stimulated endothelial cells suppresses BMP4-induced osteoblast differentiation via paracrine signaling. Together, these findings uncover a novel endothelial-to-osteoblast regulatory axis mediated by PIEZO1-GREM1-BMP4 signaling, and underscore the context-dependent effects of PIEZO1 activation on bone regeneration.
2026-06-26 | GSE300883 | GEO
Project description:The propeller-shaped blades of the PIEZO1 and PIEZO2 ion channels partition into the plasma membrane and respond to indentation or stretching of the lipid bilayer, thus converting mechanical forces into signals that can be interpreted by cells, in the form of calcium flux and changes in membrane potential. While PIEZO channels participate in diverse physiological processes, from sensing the shear stress of blood flow in the vasculature to detecting a light touch on the surface of the skin, the molecular details that enable these mechanosensors to tune their responses over a vast dynamic range of forces remain largely uncharacterized. To survey the molecular landscape surrounding PIEZO channels at the cell surface, we employed a mass spectrometry-based proteomic approach to capture and identify extracellularly exposed proteins in the vicinity of PIEZO1. This PIEZO1-proximal interactome was enriched in surface proteins localized to cell junctions and signaling hubs within the plasma membrane. Functional screening of these interaction candidates by calcium imaging and electrophysiology in an overexpression system identified the adhesion molecule CADM1/SynCAM that slows the inactivation kinetics of PIEZO1 with little effect on PIEZO2. Conversely, we found that CADM1 knockdown accelerates inactivation of endogenous PIEZO1 in Neuro-2a cells. Systematic deletion of CADM1 domains indicate that the transmembrane region is critical for the observed effects on PIEZO1, suggesting that modulation of inactivation is mediated by interactions in or near the lipid bilayer.
2024-10-30 | PXD054618 | Pride