Agonist-induced Piezo1 activation suppresses migration of transformed fibroblasts

Chubinskiy-Nadezhdin, V. I.; Vasileva, Valeria; Vassilieva, Irina O.; Sudarikova, Anastasia V.; Morachevskaya, E. A.; Negulyaev, Yuri A.

doi:10.1016/j.bbrc.2019.04.139

Cited by 52 publications

(37 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is possible that GsMTx4 modulates integrin affinity in reactive astrocytes, thus enhancing collective cell migration velocity. In agreement with our findings, Chubinskiy‐Nadezhdin et al () have also recently reported that Yoda1 decreases fibroblast migratory speed. Therefore, we hypothesize that activation of Piezo1 may attenuate the reactive phenotype of astrocytes in vivo by dampening their migratory capacity in neuroinflammatory disorders of the ageing brain, for example.…”

Section: Discussionsupporting

confidence: 94%

“…Neither activation nor inhibition of Piezo1 affected cell viability (Figure a) or mitochondrial stress (Figure b). Because Piezo1 channels have been shown previously to regulate endothelial (Eisenhoffer et al, ), fibroblast (Chubinskiy‐Nadezhdin et al, ) and cancer cell migration (McHugh, Murdoch, Haslett, & Sethi, ), we next investigated if Piezo1 channels modulate astrocyte migration. Control astrocytes were grown to confluency over a 500 μm silicone strip running down the center of a 35 mm cell culture well.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Piezo1 regulates calcium oscillations and cytokine release from astrocytes

Velasco‐Estevez

Rolle

Mampay

et al. 2019

Glia

View full text Add to dashboard Cite

Astrocytes are important for information processing in the brain and they achieve this by fine‐tuning neuronal communication via continuous uptake and release of biochemical modulators of neurotransmission and synaptic plasticity. Often overlooked are their important functions in mechanosensation. Indeed, astrocytes can detect pathophysiological changes in the mechanical properties of injured, ageing, or degenerating brain tissue. We have recently shown that astrocytes surrounding mechanically‐stiff amyloid plaques upregulate the mechanosensitive ion channel, Piezo1. Moreover, ageing transgenic Alzheimer's rats harboring a chronic peripheral bacterial infection displayed enhanced Piezo1 expression in amyloid plaque‐reactive astrocytes of the hippocampus and cerebral cortex. Here, we have shown that the bacterial endotoxin, lipopolysaccharide (LPS), also upregulates Piezo1 in primary mouse cortical astrocyte cultures in vitro. Activation of Piezo1, via the small molecule agonist Yoda1, enhanced Ca2+ influx in both control and LPS‐stimulated astrocytes. Moreover, Yoda1 augmented intracellular Ca2+ oscillations but decreased subsequent Ca2+ influx in response to adenosine triphosphate (ATP) stimulation. Neither blocking nor activating Piezo1 affected cell viability. However, LPS‐stimulated astrocyte cultures exposed to the Piezo1 activator, Yoda1, migrated significantly slower than reactive astrocytes treated with the mechanosensitive channel‐blocking peptide, GsMTx4. Furthermore, our data show that activating Piezo1 channels inhibits the release of cytokines and chemokines, such as IL‐1β, TNFα, and fractalkine (CX3CL1), from LPS‐stimulated astrocyte cultures. Taken together, our results suggest that astrocytic Piezo1 upregulation may act to dampen neuroinflammation and could be a useful drug target for neuroinflammatory disorders of the brain.

show abstract

Section: Discussionsupporting

confidence: 94%

Section: Resultsmentioning

confidence: 99%

Piezo1 regulates calcium oscillations and cytokine release from astrocytes

Velasco‐Estevez

Rolle

Mampay

et al. 2019

Glia

View full text Add to dashboard Cite

show abstract

“…Employing the Piezo1 activator Yoda1, we showed a dose-dependent change in the motility of PSCs plated on a two-dimensional matrix, with enhanced cell migration at lower concentrations and inhibition at high concentrations (Figure 3). In contrast, a recent study focused on transformed fibroblasts (Chubinskiy-Nadezhdin et al, 2019) found that similar concentrations of Yoda1 inhibit collective cell migration in wound healing in a dose-dependent manner. Those experiments investigated directed collective cell migration toward the mechano-chemical gradient in wound healing assay.…”

Section: Discussionmentioning

confidence: 79%

“…The open probability of Piezo1 can be allosterically enhanced by the small-molecular agonist Yoda1 (Syeda et al, 2015), which is known to induce Ca 2+ influx in transformed fibroblasts and myofibroblasts (Blythe et al, 2019;Chubinskiy-Nadezhdin et al, 2019). In contrast, Piezo1 can be inhibited by rendering it in an inactive conformation by extracellular acidification below pH 6.9, as demonstrated by a thorough patch clamp study (Bae et al, 2015).…”

Section: Introductionmentioning

confidence: 98%

Protonation of Piezo1 Impairs Cell-Matrix Interactions of Pancreatic Stellate Cells

et al. 2020

View full text Add to dashboard Cite

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an acidic and fibrotic stroma. The extracellular matrix (ECM) causing the fibrosis is primarily formed by pancreatic stellate cells (PSCs). The effects of the altered biomechanics and pH landscape in the pathogenesis of PDAC, however, are poorly understood. Mechanotransduction in cells has been linked to the function of mechanosensitive ion channels such as Piezo1. Here, we tested whether this channel plays crucial roles in transducing mechanical signals in the acidic PDAC microenvironment. We performed immunofluorescence, Ca 2+ influx and intracellular pH measurements in PSCs and complemented them by live-cell imaging migration experiments in order to assess the function of Piezo1 channels in PSCs. We evaluated whether Piezo1 responds to changes of extracellular and/or intracellular pH in the pathophysiological range (pH 6.6 and pH 6.9, respectively). We validated our results using Piezo1-transfected HEK293 cells as a model system. Indeed, acidification of the intracellular space severely inhibits Piezo1-mediated Ca 2+ influx into PSCs. In addition, stimulation of Piezo1 channels with its activator Yoda1 accelerates migration of PSCs on a two-dimensional ECM as well as in a 3D setting. Furthermore, Yoda1-activated PSCs transmit more force to the surrounding ECM under physiological pH, as revealed by measuring the dislocation of microbeads embedded in the surrounding matrix. This is paralleled by an enhanced phosphorylation of myosin light chain isoform 9 after Piezo1 stimulation. Intriguingly, upon acidification, Piezo1 activation leads to the initiation of cell death and disruption of PSC spheroids. In summary, stimulating Piezo1 activates PSCs by inducing Ca 2+ influx which in turn alters the cytoskeletal architecture. This results in increased cellular motility and ECM traction, which can be useful for the cells to invade the surroundings and to detach from the tissue. However, in the presence of an acidic extracellular pH, although net Ca 2+ influx is reduced, Piezo1 activation leads to severe cell stress also limiting cellular viability. In conclusion, our results indicate a strong interdependence between environmental pH, the mechanical output of PSCs and stromal mechanics, which promotes early local invasion of PDAC cells.

show abstract

“…Malignant tumor cells are characterized by migration, invasion, and metastasis (Chubinskiy-Nadezhdin et al 2019). Tumor cell mobility is affected by a variety of signaling cascades, including ion channels and transporters (Schwab and Stock 2014).…”

Section: Introductionmentioning

confidence: 99%

The function of Piezo1 in colon cancer metastasis and its potential regulatory mechanism

Sun

Liu

et al. 2020

J Cancer Res Clin Oncol

View full text Add to dashboard Cite

Objective Increasing evidence has revealed that mechanical stress and elevated mechanical signals promote malignant tumor transformation and metastasis. This study aimed to explore the function of the mechanically activated ion-channel Piezo1 in the colon cancer metastasis and its potential regulatory mechanism. Methods First, we examined the expression levels of Piezo1 and mitochondrial calcium uniporter (MCU) both in colon cancer tissues and assessed the prognostic value of Piezo1 and MCU in a colon cancer cohort (n = 110). Second, functional assays were performed to investigate the effects of Piezo1 and MCU on colon cancer cell migration, invasion, and mitochondrial membrane potential. Third, we analyzed the expression of Piezo1, MCU, and HIF-1α by overexpressing/silencing each other's expression. Results We found that Piezo1 was up-regulated and MCU was down-regulated in colon cancer tissues. Piezo1 and MCU were both correlated with poor prognosis of patients with colon cancer. Overexpressing Piezo1 and silencing MCU could promote colon cancer cell migration and metastasis, reduce mitochondrial membrane potential, and promote each other's expression. We also found that HIF-1α was up-regulated in colon cancer tissues. Additionally, silencing Piezo1 inhibited the expression of HIF-1α and VEGF, which was contrary to MCU silencing. Intriguingly, Piezo1-overexpressing cells did not regain their migration behaviors when HIF-1α expression was inhibited, which was accompanied with the re-expression of MCU and VEGF. Conclusion In our study, Piezo1 is involved in colon cancer cell metastasis. Furthermore, our findings indicated a possible Piezo1-MCU-HIF-1α-VEGF axis, which still need further exploration.Keywords Colon cancer · Metastasis · Piezo1 · Mitochondrial calcium uniporter · HIF-1α Yanhua Sun and Ming Li have contributed equally to this work.

show abstract

Agonist-induced Piezo1 activation suppresses migration of transformed fibroblasts

Cited by 52 publications

References 22 publications

Piezo1 regulates calcium oscillations and cytokine release from astrocytes

Piezo1 regulates calcium oscillations and cytokine release from astrocytes

Protonation of Piezo1 Impairs Cell-Matrix Interactions of Pancreatic Stellate Cells

The function of Piezo1 in colon cancer metastasis and its potential regulatory mechanism

Contact Info

Product

Resources

About