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The chondrocyte “mechanome”: Activation of the mechanosensitive ion channels TRPV4 and PIEZO1 drives unique transcriptional signatures

ABSTRACT: The chondrocyte “mechanome”: Activation of the mechanosensitive ion channels TRPV4 and PIEZO1 drives unique transcriptional signatures

PROVIDER: PRJNA1120429 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR29297200_1.fastq.gz	Fastqsanger.gz
	SRR29297200_2.fastq.gz	Fastqsanger.gz
	SRR29297201_1.fastq.gz	Fastqsanger.gz
	SRR29297201_2.fastq.gz	Fastqsanger.gz
	SRR29297202_1.fastq.gz	Fastqsanger.gz

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The chondrocyte “mechanome”: Activation of the mechanosensitive ion channels TRPV4 and PIEZO1 drives unique transcriptional signatures

Project description:The mechanosensitive ion channels Transient Receptor Potential Vanilloid 4 (TRPV4) and PIEZO1 transduce physiologic and supraphysiologic magnitudes of mechanical signals in the chondrocyte, respectively. TRPV4 activation promotes chondrogenesis, while PIEZO1 activation by supraphysiologic deformations drives cell death. The mechanisms by which activation of these channels discretely drives changes in gene expression to alter cell behavior remains to be determined. To date, no studies have contrasted the transcriptomic response to activation of these channels, nor has any published data attempted to correlate these transcriptomes to alterations in cellular function. This study used RNA sequencing to comprehensively investigate the transcriptomes associated with activation of TRPV4 or PIEZO1, revealing that TRPV4 and PIEZO drive distinct transcriptomes, but also exhibit unique co-regulated clusters of genes. Notably, activation of PIEZO1 through supraphysiologic deformation induced a transient inflammatory profile that overlapped with the interleukin (IL)-1-responsive transcriptome and contained genes associated with cartilage degradation and osteoarthritis progression. However, both TRPV4 and PIEZO1 were also shown to elicit anabolic effects. PIEZO1 expression promoted a pro-chondrogenic transcriptome under unloaded conditions, and daily treatment with PIEZO1 agonist Yoda1 significantly increased sulfated glycosaminoglycan deposition in vitro. These findings emphasize the presence of a broad “mechanome” with distinct effects of TRPV4 and PIEZO1 activation in chondrocytes, suggesting complex roles for PIEZO1 in both the physiologic and pathologic responses of chondrocytes. The identification of transcriptomic profiles unique to or shared by PIEZO1 and TRPV4 (distinct from IL-1-induced inflammation) could inform future therapeutic designs targeting these channels for the management and treatment of osteoarthritis.

2024-06-05 | GSE269159 | GEO

CFTR deficiency modulates the activity of endothelial mechanosensitive channels TRPV4 and PIEZO1; and drives endothelial barrier failure.

Project description:Cystic fibrosis (CF) is a life-shortening genetic disease caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Despite reports of CFTR expression on endothelial cells, pulmonary vascular perturbations, and perfusion deficit in CF patients, the mechanism of pulmonary vascular disease in CF remains unclear. Here, we describe loss of small pulmonary blood vessels in CF patients with severe lung disease. Using a vessel-on-a-chip model, we establish a shear stress-dependent mechanism of endothelial barrier failure in CF involving calcium-permeable mechanosensitive channel TRPV4. Furthermore, we demonstrate that CFTR deficiency downregulates the function of PIEZO1, another calcium-permeable mechanosensitive channel involved in angiogenesis and wound repair, and further exacerbates loss of small pulmonary blood vessels. We show that CFTR directly interacts with PIEZO1 and enhances its function, and that CFTR deficiency reduces PIEZO1 activity. Our study identifies key cellular targets to mitigate loss of small pulmonary blood vessels in CF.

2024-09-18 | GSE244214 | GEO

CFTR deficiency modulates the activity of endothelial mechanosensitive channels TRPV4 and PIEZO1 and drives endothelial barrier failure.

Project description:CFTR deficiency modulates the activity of endothelial mechanosensitive channels TRPV4 and PIEZO1 and drives endothelial barrier failure.

| PRJNA1021680 | ENA

In vitro Examination of Piezo1-TRPV4 Dynamics: Implications for Placental Endothelial Function in Normal and Preeclamptic Pregnancies

Project description:Mechanosensation is essential for endothelial cell (EC) function, which is compromised in early-onset preeclampsia (EPE) impacting offspring health. The ion channels Piezo1 and TRPV4 are co-regulated mechanosensors in ECs. Here we show functional co-expression of both channels in feto-placental ECs (fpECs) and that calcium influx and membrane depolarization in response to chemical channel activation is reduced in EPE fpECs. Downstream of channel activation, Piezo1 alone can induce phosphorylation of endothelial nitric oxide synthase (eNOS) in fpECs, while combined activation of Piezo1 and TRPV4 only affects eNOS phosphorylation in EPE fpECs. Additionally, combined activation reduces the barrier integrity of fpECs, also with a stronger effect in EPE fpECs. This implies altered Piezo1-TRPV4 co-regulation in EPE. Mechanistically, we suggest this to be driven by changes in the arachidonic acid metabolism in EPE fpECs as identified by RNA-Seq. Targeting of Piezo1 and TRPV4 might hold potential for EPE treatment options in the future.

2024-12-12 | GSE274555 | GEO

Piezo1 channels restrain ILC2s and regulate the development of airway hyperactivity [yoda1]

Project description:Mechanosensitive ion channels sense force and pressure in immune cells to drive the inflammatory response in highly mechanical organs. Here we report that Piezo1 channels repress group 2 innate lymphoid cells (ILC2s)-driven type 2 inflammation in the lungs. Piezo1 is induced on lung ILC2s upon activation, as genetic ablation of Piezo1 in ILC2s increases their function and exacerbates the development of airway hyperreactivity (AHR). Conversely, Piezo1 agonist Yoda1 reduces ILC2-driven lung inflammation. Mechanistically, Yoda1 inhibits ILC2 cytokine secretion and proliferation in a KLF2-dependent manner, as we further found that Piezo1 engagement reduces ILC2 oxidative metabolism. Consequently, in vivo Yoda1 treatment notably reduces the development of AHR in experimental models of ILC2-driven allergic asthma. Human circulating ILC2s express and induce Piezo1 upon activation, as Yoda1 treatment of humanized mice reduces human ILC2-driven AHR. Our studies define Piezo1 as a critical regulator of ILC2s and we propose the potential of Piezo1 activation as a novel therapeutic approach for the treatment of ILC2-driven allergic asthma.

2024-02-20 | GSE255881 | GEO

Piezo1 channels restrain ILC2s and regulate the development of airway hyperactivity [piezo1KO]

2024-02-20 | GSE255882 | GEO

Three-Dimensional Matrix Stiffness Modulates Mechanosensitive and Phenotypic Alterations in Oral Squamous Cell Carcinoma Spheroids

Project description:Extracellular biophysical cues such as matrix stiffness are key stimuli tuning cell fate and affecting tumor progression in vivo. However, it remains unclear how spheroids in a 3D microenvironment perceive matrix mechanical stiffness stimuli and translate them into intracellular signals driving cancer. Mechanosensitive Piezo1 and TRPV4 ion channels, upregulated in many malignancies, are major transducers of such physical stimuli into biochemical responses. Most mechanotransduction studies probing the reception of changing stiffness cues by cells are, however, still limited to 2D culture systems or cell-extracellular matrix models which lack the major cell-cell interactions prevalent in 3D cancer tumors. Here, we engineered a 3D spheroid culture environment with varying mechanobiological properties to study the effect of static matrix stiffness stimuli on mechanosensitive and malignant phenotypes in oral squamous cell carcinoma spheroids. We find that spheroid growth is enhanced when cultured in stiff extracellular matrix. Using flow cytometry, we show that the expression of mechanoreceptor Piezo1 and stemness marker CD44 is upregulated in stiff matrix. We also report the upregulation of a selection of genes with associations to mechanoreception, ion channel transport, extracellular matrix organization, and tumorigenic phenotypes in stiff matrix spheroids. Together, our results indicate that cancer cells in 3D spheroids utilize mechanosensitive ion channels Piezo1 and TRPV4 to sense changes in static extracellular matrix stiffness and that stiffness drives pro-tumorigenic phenotypes in oral squamous cell carcinoma.

2024-03-28 | GSE262142 | GEO

Mechanosensitive Piezo1 is crucial for periosteal stem cell-mediated fracture healing

Project description:Mechanosensitive Piezo1 is crucial for periosteal stem cell-mediated fracture healing

2024-12-19 | GSE266774 | GEO

Mechanosensitive ion channel regulates tissue stiffening to promote glioma aggression

Project description:Tissue stiffening is a physical hallmark of solid tumor. In our study, we found that the mechanosensitive ion channel PIEZO1 can be tumor cells force sensor and transducer that regulate the altered tissue mechanics. We examined the transcriptional changes modulated by depletion of PIEZO1 in two human GBM cell lines. We found that with PIEZO1 KD, the components involved in ECM organization, focal adhesion formation, cytoskeleton, and mitosis, which contribute to tissue stiffness, are down-regulated.

2018-10-18 | GSE113261 | GEO

Gene expression profile of TGFβ3 stimulation and TRPV4 activation/inhibition in the TC28a2 human chondrocyte cell line

Project description:RNA-seq of TC28a2 cells following TRPV4 activation/inhibition in the presence and absence of prior TGFβ3 stimulation. The experiment was performed to determine the effect of TRPV4 activity on gene expression in the presence and absence of TGFβ stimulation. TGFβ3 was used to stimulate TGFβ signalling, GSK1016790A (GSK101) was used to activate TRPV4, GSK2193874 (GSK219) was used to inhibit TRPV4 and DMSO was used as a vehicle control.

2022-01-17 | E-MTAB-10279 | biostudies-arrayexpress

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