Ion Channel Piezo1 Research Articles

Piezo1-directed neutrophil extracellular traps regulate macrophage differentiation during influenza virus infection

Neutrophils and macrophages are critical for antiviral immunity, but their reciprocal regulatory roles and mechanisms in the response to viral infection remain unclear. Herein, we found that the ion channel Piezo1 directs neutrophil extracellular trap (NET) formation and regulates macrophage functional differentiation in anti-influenza virus immunity. Genetic deletion of Piezo1 in neutrophils inhibited the generation of NETs and M1 macrophage differentiation while driving the development of M2 macrophages during viral infection. Piezo1-directed neutrophil NET DNA directly regulates macrophage differentiation in vitro and in vivo. Mechanistically, neutrophil Piezo1 deficiency inhibited NET DNA production, leading to decreased TLR9 and cGAS-STING signalling activity while inducing reciprocal differentiation from M1 to M2 macrophages. In addition, Piezo1 integrates magnesium signalling and the SIRT2-hypoxia-inducible factor-1 alpha (HIF1α)-dependent pathway to orchestrate reciprocal M1 and M2 macrophage lineage commitment through neutrophil-derived NET DNA. Our studies provide critical insight into the role of neutrophil-based mechanical regulation of immunopathology in directing macrophage lineage commitment during the response to influenza virus infection.

Chewing-Activated TRPV4/PIEZO1-HIF-1α-Zn Axes in a Rat Periodontal Complex.

The upstream mechanobiological pathways that regulate the downstream mineralization rates in periodontal tissues are limitedly understood. Herein, we spatially colocalized and correlated compression and tension strain profiles with the expressions of mechanosensory ion channels (MS-ion) TRPV4 and PIEZO1, biometal zinc, mitochondrial function marker (MFN2), cell senescence indicator (p16), and oxygen status marker hypoxia-inducible factor-1α (HIF-1α) in rats fed hard and soft foods. The observed zinc and related cellular homeostasis in vivo were ascertained by TRPV4 and PIEZO1 agonists and antagonists on human periodontal ligament fibroblasts ex vivo. Four-week-old male Sprague-Dawley rats were fed hard (n = 3) or soft (n = 3) foods for 4 wk (in vivo). Significant changes in alveolar socket and root shapes with decreased periodontal ligament space and increased cementum volume fraction were observed in maxillae on reduced loads (soft food). Reduced loads impaired distally localized compression-stimulated PIEZO1 and mesially localized tension-stimulated TRPV4, decreased mitochondrial function (MFN2), and increased cell senescence in mesial and distal periodontal regions. The switch in HIF-1α from hard food-distal to soft food-mesial indicated a plausible effect of shear-regulated blood and oxygen flows in the periodontal complex. Blunting or activating TRPV4 or PIEZO1 MS-ion channels by channel-specific antagonists or agonists in human periodontal ligament fibroblast cultures (in vitro) indicated a positive correlation between zinc levels and zinc transporters but not with MS-ion channel expressions. The effects of reduced chewing loads in vivo were analogous to TRPV4 and PIEZO1 antagonists in vitro. Study results collectively illustrated that tension-induced TRPV4 and compression-induced PIEZO1 activations are necessary for cell metabolism. An increased hypoxic state with reduced functional loads can be a conducive environment for cementum growth. From a practical standpoint, dose rate-controlled loads can modulate tension and compression-specific MS-ion channel activation, cellular zinc, and HIF-1α transcription. These mechanobiochemical events indicate the plausible catalytic role of biometal zinc in mineralization, periodontal maintenance, and dentoalveolar joint function.

GsMTx-4 combined with exercise improves skeletal muscle structure and motor function in rats with spinal cord injury.

Motor dysfunction and muscle atrophy are typical symptoms of patients with spinal cord injury (SCI). Exercise training is a conventional physical therapy after SCI, but exercise intervention alone may have limited efficacy in reducing secondary injury and promoting nerve regeneration and functional remodeling. Our previous research found that intramedullary pressure after SCI is one of the key factors affecting functional prognosis. It has been reported that GsMTx-4, a specific blocker of the mechanosensitive ion channels Piezo1, can protect the integrity of the neuromuscular junction and promote nerve regeneration, and thus has the potential as a therapeutic agent for SCI. In this study, we observed the combined and separate therapeutic effect of GsMTx-4 and exercise on the structure of the soleus muscle and motor function in rats with SCI. At 42 days post-injury, compared with SCI rats, the Basso-Beattie-Bresnahan score (P = 0.0007) and Gait Symmetry (P = 0.0002) were significantly improved after combination therapy. On histology of rat soleus muscle, compared with SCI rats, the combined treatment significantly increased the wet weight ratio, muscle fiber cross-sectional area and acetylcholinesterase (all P<0.0001). On histology of rat spinal tissue, compared with SCI rats, the combined treatment significantly increased neuron counts and BDNF levels, and significantly reduced the percentage of TUNEL-positive cells (all P<0.0001). On physiology of rat soleus muscle, compared with SCI rats, the combined treatment increased the succinate dehydrogenase expression (P<0.0001), while the expression of α-glycerophosphate dehydrogenase (P<0.0001) and GDF8 protein (P = 0.0008) decreased. Results indicate the combination therapy effectively improves histopathology of spinal cord and soleus muscle in SCI rats, enhancing motor function. This study was conducted on animal models, it offers insights for SCI treatment, advancing understanding of lower limb muscle pathology post-SCI. Further research is needed for clinical validation in the future.

Single-particle tracking reveals heterogeneous PIEZO1 diffusion.

The mechanically-activated ion channel PIEZO1 is critical to numerous physiological processes, and is activated by diverse mechanical cues. The channel is gated by membrane tension and has been found to be mobile in the plasma membrane. We employed single particle tracking (SPT) of endogenous, tdTomato-tagged PIEZO1 using Total Internal Reflection Fluorescence Microscopy in live cells. Application of SPT unveiled a surprising heterogeneity of diffusing PIEZO1 subpopulations, which we labeled "mobile" and "immobile". We sorted these trajectories into the two aforementioned categories using trajectory spread. To evaluate the effects of the plasma membrane composition on PIEZO1 diffusion, we manipulated membrane composition by depleting or supplementing cholesterol, or by adding margaric acid to stiffen the membrane. To examine effects of channel activation on PIEZO1 mobility, we treated cells with Yoda1, a PIEZO1 agonist, and GsMTx-4, a channel inhibitor. We collected thousands of trajectories for each condition, and found that cholesterol removal and Yoda1 incubation increased the channel's propensity for mobility. Conversely, we found that GsMTx-4 incubation and cholesterol supplementation resulted in a lower chance of mobile trajectories, whereas margaric acid incubation did not have a significant effect on PIEZO1 mobility. The "mobile" trajectories were analyzed further by fitting the time-averaged mean-squared displacement as a function of lag time to a power-law model, revealing mobile PIEZO1 puncta exhibit anomalous subdiffusion. These studies illuminate the fundamental properties governing PIEZO1 diffusion in the plasma membrane and set the stage to determine how cellular processes and interactions may influence channel activity and mobility.

Polyunsaturated fatty acids suppress PIEZO ion channel mechanotransduction in articular chondrocytes.

Osteoarthritis (OA) is characterized by articular cartilage degeneration, leading to pain and loss of joint function. Recent studies have demonstrated that omega-3 (ω3) polyunsaturated fatty acid (PUFA) supplementation can decrease injury-induced OA progression in mice fed a high-fat diet. Furthermore, PUFAs have been shown to influence the mechanical properties of chondrocyte membranes, suggesting that alterations in mechanosensitive ion channel signaling could contribute to the mechanism by which ω3 PUFAs decreased OA pathogenesis. Here, we hypothesized that PUFAs may alter mechanical signaling through PIEZO1 (activated by changes in membrane tension) and TRPV4 (activated by physiologic mechano-osmotic signals), as these mechanosensitive cation channels have been shown to influence OA progression. Our results demonstrated that PUFAs reduced chondrocyte sensitivity to single-cell mechanical compression and to pharmacologic agonists of PIEZO1 and TRPV4, with ω3 PUFAs having the most significant effects overall. We also found that supplementation with ω6 PUFA linoleic acid (LA) altered the biophysical properties of chondrocytes, as evidenced by increased intracellular lipid droplet formation and more rapid membrane rupture in response to hypo-osmotic shock, suggesting that LA increases chondrocyte membrane susceptibility to damage. Our findings underscore the differential impacts of specific PUFAs on chondrocyte signaling and membrane properties and provide important considerations in the development of nutritional interventions to prevent or treat OA.

Piezo Ion Channels and Their Association With Haptic Technology Use: A Narrative Review.

The recent identification of Piezo ion channels demonstrating a mechano-sensitive impact on neurons revealed distinct Piezo-1 and 2 types. While Piezo-1 predominates in neurons linked to non-sensory stimulation, such as pressure in blood vessels, Piezo-2 predominates in neurons linked to sensory stimulation, such as touch. Piezo-1 and 2 have a major bidirectional impact on transient receptor potential (TRP) ion channels, and TRPs also impact neurotransmitter release. Particularly existent in dorsal root ganglion (DRG) neurons, which are located in nerve endings, Piezo-2 is a key DRG activator. Subsequent Piezo findings have been vital to recent medical haptic technology developments, in tandem with breakthroughs in the emerging neurology subfield of connectomics plus AI developments. Included in this review are a historical Piezo overview, the interrelationship of Piezo channels with TRPs, inclusive of TRPV1/TRPV8, the impact on medical and rehab haptic technology, a focus on haptic technology use in stroke survivor rehab inclusive of pain mitigation, and the development of a haptic technology patch aimed at alleviating pain and/or anxiety. Neurogenic pain resulting from hyperalgesia/allodynia in stroke survivors is a potential target for drugs and haptics aimed at pain reduction; patients experiencing neuropathic or psychosomatic pain are other prime targets. Increased Piezo knowledge may promote more precisely targeted haptic therapeutic developments.

Piezo1 expression in mature osteocytes is dispensable for the skeletal response to mechanical loading

Mechanical loading is essential for bone growth and homeostasis, with osteocytes considered the primary mechanosensors. Deleting the mechanosensitive ion channel Piezo1 from Dmp1-Cre-targeted cells, which include both osteoblasts and osteocytes, resulted in reduced bone mass and impaired skeletal responses to mechanical stimuli. To specifically isolate Piezo1's role in osteocytes, we used Sost-Cre mice to generate mice with Piezo1 deletion exclusively in mature osteocytes. These mice exhibited lower bone mineral density, decreased cancellous bone mass, and reduced cortical thickness with decrease periosteal expansion. However, unlike mice lacking Piezo1 in both osteoblasts and osteocytes, those with Piezo1 deletion in mature osteocytes responded normally to mechanical loading. These findings suggest that Piezo1 expression in mature osteocytes contributes to bone maintenance under normal physiological condition, but is dispensable for the skeletal response to mechanical loading.

Sonogenetics is a novel antiarrhythmic mechanism.

Arrhythmia of the heart is a dangerous and potentially fatal condition. The current widely used treatment is the implantable cardioverter defibrillator (ICD), but it is invasive and affects the patient's quality of life. The sonogenetic mechanism proposed here focuses ultrasound on a cardiac tissue, controls endogenous stretch-activated Piezo1 ion channels on the focal region's cardiomyocyte sarcolemma, and restores normal heart rhythm. In contrast to anchoring the implanted ICD lead at a fixed position in the myocardium, the size and position of the ultrasound focal region can be selected dynamically by adjusting the signals of every piezoelectric chip on the ultrasonic phased array, and it allows novel and efficient defibrillations. Based on the developed interdisciplinary electro-mechanical model of sonogenetic treatment, our analysis shows that the proposed ultrasound intensity and frequency will be safe and painless for humans and well below the limits established by the U.S. Food and Drug Administration.

GsMTx4 Combined with Exercise Exerts Neuroprotective Effects by Regulating Neuronal Autophagy in Rats with Spinal Cord Injury.

A sharp increase in intramedullary pressure after spinal cord injury (SCI) can aggravate secondary injury and lead to severe neurological deficits. Unfortunately, effective treatment options are currently lacking. The mechanosensitive ion channel Piezo1 plays an important role in the pathological process of SCI by transducing mechanical stress. The Piezo1 inhibitor GsMTx4 has been shown to have neuroprotective effects and may hold therapeutic potential for SCI. Given that single drug treatment strategy has limited effect on functional recovery after SCI, we explored the efficacy of combining GsMTx4 with exercise training in treating SCI in rats and investigated the underlying mechanisms. We used the T10 SCI rat model, administered GsMTx4 immediately after injury, and performed 4weeks of body weight supported treadmill training starting (BWSTT) 2weeks post injury. Subsequently, HE and LFB staining were used to observe the morphology of spinal cord tissue, WB was used to detect autophagy and apoptosis-related proteins, biochemical detection of calcium ion concentration and CTSD activity, IHC detection of LAMP1 expression, immunofluorescence labeling of NeuN and ChAT-positive motor neurons, as well as MBP and GFAP, and BBB scores were used to evaluate rat motor function. We found that the combined treatment of GsMTx4 drug and exercise training was more effective than single treatment alone. The combined treatment reduced calcium ion concentration, improved lysosomal function, enhanced autophagic flux, reduced cell apoptosis, and significantly improved the motor function of rats. This combined treatment regimen may pave the way for developing more comprehensive treatment strategies for SCI in the future.

Repair Effect of siRNA Double Silencing of the Novel Mechanically Sensitive Ion Channels Piezo1 and TRPV4 on an Osteoarthritis Rat Model.

This study aimed to explore the repair effect of siRNA-mediated double silencing of the mechanically sensitive ion channels Piezo1 and TRPV4 proteins on a rat model of osteoarthritis. Piezo1 and TRPV4 interference plasmids were constructed using siRNA technology. Sprague Dawley (SD) rats were divided into four groups: the model group, siRNA-Piezo1, siRNA-TRPV4, and double gene silencing groups. Improved Mankin and OARSI scores were calculated based on H&E staining and Safranin O-fast green staining. Immunohistochemical staining was used to determine expression levels of aggrecan and Collagen II proteins. Piezo1, TRPV4, Aggrecan, and Collagen II mRNA expression in knee joint cartilage tissue were assessed using qRT-PCR. Lentivirus-mediated siRNA plasmids (siRNA-Piezo1, siRNA-TRPV4, and double-gene siRNA silencing plasmids) achieved > 90% transfection efficiency in chondrocytes. RT-PCR results indicated that double-gene siRNA silencing plasmids silenced Piezo1 and TRPV4 mRNA expression (P < 0.05). Modified Mankin and OARSI scores revealed that the repair effect in the double gene silencing group was significantly better than that of the siRNA-Piezo1 and siRNA-TRPV4 groups (P < 0.05). Relative expression of aggrecan and collagen II mRNA in the double gene-silenced group was significantly higher than in the siRNA-Piezo1 and siRNA-TRPV4 groups (P < 0.05). Double silencing Piezo1 and TRPV4 plays a key role in cartilage repair in an osteoarthritic rat model by promoting the expression of Aggrecan and Collagen II.

Amyloid beta Aβ1-40 activates Piezo1 channels in brain capillary endothelial cells.

Amyloid-beta (Aβ) peptide accumulation on blood vessels in the brain is a hallmark of neurodegeneration. While Aβ peptides constrict cerebral arteries and arterioles, their impact on capillaries is less understood. Aβ was recently shown to constrict brain capillaries through pericyte contraction, but whether-and if so how-Aβ affects endothelial cells (ECs) remains unknown. ECs represent the predominant vascular cell type in the cerebral circulation, and we recently showed that the mechanosensitive ion channel Piezo1 is functionally expressed in the plasma membrane of ECs. Since Aβ disrupts membrane structures, we hypothesized that Aβ1-40, the predominantly deposited isoform in the cerebral circulation, alters endothelial Piezo1 function. Using patch clamp electrophysiology and freshly isolated capillary ECs, we assessed the impact of Aβ1-40 peptide on single-channel Piezo1 activity. We show that Aβ1-40 increased Piezo1 open probability and the channel open time. Aβ1-40 effects were absent when Piezo1 was genetically deleted or when a superoxide dismutase/catalase mimetic was used. Further, Aβ1-40 enhanced Piezo1 mechanosensitivity and lowered the pressure of half-maximal Piezo1 activation. Our data collectively suggest that Aβ1-40 facilitates higher Piezo1-mediated cation influx in brain ECs. These novel findings have the potential to unravel the possible involvement of Piezo1 modulation in the pathophysiology of neurodegenerative diseases characterized by Aβ accumulation.

Piezo1, but not ATP, is required for mechanotransduction by bladder mucosal afferents in cystitis

Piezo ion channels play a role in bladder sensation, but the sensory afferent subtypes that utilise Piezo channels have not been fully explored. We made single-unit extracellular recordings from mucosal-projecting bladder afferents in guinea pigs with protamine/zymosan-induced cystitis. The Piezo1 agonist, Yoda1, significantly potentiated mechanosensitivity, while its antagonist, Dooku1, abolished this potentiation. The P2 purinoceptor antagonist, PPADS abolished α,β-methylene ATP-induced excitation of mucosal afferents without affecting their mechanical activation or potentiation of mechanosensitivity by Yoda1. The findings suggest Piezo1, but not ATP, is required for mechanotransduction in bladder mucosal afferents in cystitis.

PIEZO1 overexpression in hereditary hemorrhagic telangiectasia arteriovenous malformations.

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 due to overactivation of VEGFR2/PI3K/AKT signaling pathways. However, the full spectrum of signaling alterations in Alk1 mutants remains unknown and means to combat AVM formation in patients are yet to be developed. Single-cell RNA sequencing of endothelial-specific Alk1 KO mouse retinas and controls identified a cluster of endothelial cells (ECs) that was unique to Alk1 mutants and that overexpressed fluid shear stress (FSS) signaling signatures including upregulation of the mechanosensitive ion channel PIEZO1. PIEZO1 overexpression was confirmed in human HHT lesions, and genetic and pharmacological PIEZO1 inhibition was tested in Alk1 KO mice, as well as downstream PIEZO1 signaling. Pharmacological PIEZO1 inhibition, and genetic Piezo1 deletion in Alk1 -deficient mice effectively mitigated AVM formation. Furthermore, we identified that elevated VEGFR2/AKT, ERK5-p62-KLF4, hypoxia and proliferation signaling were significantly reduced in Alk1 - Piezo1 double ECKO mice. PIEZO1 overexpression and signaling is integral to HHT2, and 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.

TMIC-17. TARGETING THE FLUIDIC FORCE-SENSING MECHANISM TO TREAT BRAIN TUMOR METASTASIS

Abstract Biofluid flow generates fluid shear stress (FSS), a mechanical force widely present in tissue microenvironment. How brain tumor growth alters the conduit of biofluid, thereby impacting FSS-regulated cancer progression is unknown. Medulloblastoma (MB) is the most common malignant brain tumor in children. Dissemination of MB cells into the cerebrospinal fluid (CSF) initiates metastasis within the central nervous system. By simulating CSF dynamics based on magnetic resonance imaging of MB patients, we discovered that FSS is elevated at the cervicomedullary junction. Strikingly, we found that MB-relevant FSS promotes metastasis along mouse spinal cords. Mechanistically, FSS induces metastatic cell behaviours, including weakened cell-substrate adhesion, increased motility, cell clustering, and plasma membrane localization of glucose transporter 1 (GLUT1) to enhance glucose uptake. FSS is perceived by mechanosensitive ion channel PIEZO2, which drives actomyosin contractility-dependent GLUT1 recruitment at the plasma membrane. Genetic targeting of PIEZO2 or pharmacologic inhibition of GLUT1 mitigates metastasis. Collectively, these findings define a targetable FSS-activated mechano-metastatic cascade for the treatment of MB metastasis.

Mechanosensitive Ion Channel Piezo1 regulates tight junctions between endothelium and mediates the occurrence of aortic dissection

Abstract Aims Exploring whether changes in endothelial Piezo1 mechanically sensitive ion channels can lead to thoracic aortic dissection（TAD） and its specific mechanisms of action. Methods and results IF showed aberrant Piezo1 expressions in the CD31+ endothelial cells in thoracic aortas of patients with TAD. In a β-aminopropionitrile (BAPN)-induced TAD mouse model, knockout of Piezo1 in endothelial cells shows a protective effect on aortic dissection, while the crucial tight junction (TJ) components ZO-1 was significantly increased by En Face staining. For identified how the Piezo1 ion channel influences the ZO-1 between endothelium, we used mass spectrometry analysis and RNA sequencing to identify a key factor Trib1 mediating the ubiquitination degradation of ZO-1. Also, we found the low expression of Trib1 in endothelial cell of Piezo1 ECKO mouse with BAPN feeding. Finally, we rescued the expression of TRIB1 by targeting endothelial cells with AAV9-TIE2-TRIB1, demonstrating that Piezo1 indeed promotes the occurrence of aortic dissection through degrading the TRIB1-COP1-ZO-1 complex. Conclusion The activation of Piezo1 promotes the occurrence of （TAD） through Trib1 mediated degradation of endothelial tight junctions. Inhibiting endothelial Piezo has the potential to become a specific therapeutic and preventive target for（TAD）.

Ion channel Piezo1 induces ferroptosis of trabecular meshwork cells: a novel observation in the pathogenesis in primary open angle glaucoma.

This study aims to elucidate the role of Piezo1, a mechanosensitive molecule, in trabecular meshwork cells (TMCs) in the context of primary open angle glaucoma (POAG), a leading cause of irreversible visual impairment. Dysfunction of the trabecular meshwork (TM) is a key factor in the elevated intraocular pressure (IOP) observed in POAG, yet the specific mechanisms leading to TM dysfunction are not fully understood. We performed cell stretching on human trabecular meshwork cells (HTMCs) and pharmacologically activated HTMCs with Yoda1 to study the role of Piezo1 in HTMCs. We focused on assessing cell viability, mitochondrial changes, lipid peroxidation, and the expression of ferroptosis-related targets such as acyl-CoA synthetase long-chain family member 4 (ACSL4) and glutathione peroxidase 4 (GPX4). Cell stretching induces ferroptosis in HTMCs, and this phenomenon is reversed by Piezo1 knockdown. In addition, pharmacological activation of Piezo1 also leads to ferroptosis in HTMCs. Furthermore, inhibiting the JNK/p38 signaling pathway was found to mitigate the ferroptotic response induced by Yoda1, thereby confirming that Piezo1 induces ferroptosis in TMCs through this pathway. Notably, our experiments suggest that Yoda1 may trigger ferroptosis in the TM of mouse eyes. Our findings demonstrate that the Piezo1 pathway is a crucial mediator of ferroptosis in TMCs, providing new insights into the pathogenic mechanisms of glaucoma, particularly POAG. This study highlights the potential of targeting the Piezo1 pathway as a therapeutic approach for mitigating TM dysfunction and managing POAG.NEW & NOTEWORTHY This study is the first to show that cell stretching induces ferroptosis in trabecular meshwork cells (TMCs), dependent on Piezo1 activation. Targeting the Piezo1 pathway offers new therapeutic potential for mitigating trabecular meshwork dysfunction and managing primary open angle glaucoma (POAG). The study also reveals Piezo1 induces ferroptosis via the JNK/p38 signaling pathway.

Mechanosensing by Piezo1 in gastric ghrelin cells contributes to hepatic lipid homeostasis in mice.

Ghrelin is an orexigenic peptide released by gastric ghrelin cells that contributes to obesity and hepatic steatosis. The mechanosensitive ion channel Piezo1 in gastric ghrelin cells inhibits the synthesis and secretion of ghrelin in response to gastric mechanical stretch. We sought to modulate hepatic lipid metabolism by manipulating Piezo1 in gastric ghrelin cells. Mice with a ghrelin cell-specific deficiency of Piezo1 (Ghrl-Piezo1-/-) had hyperghrelinemia and hepatic steatosis when fed a low-fat or high-fat diet. In these mice, hepatic lipid accumulation was associated with changes in gene expression and in protein abundance and activity expected to increase hepatic fatty acid synthesis and decrease lipid β-oxidation. Pharmacological inhibition of the ghrelin receptor improved hepatic steatosis in Ghrl-Piezo1-/- mice, thus confirming that the phenotype of these mice was due to overproduction of ghrelin caused by inactivation of Piezo1. Gastric implantation of silicone beads to induce mechanical stretch of the stomach inhibited ghrelin synthesis and secretion, thereby helping to suppress fatty liver development induced by a high-fat diet in wild-type mice but not in Ghrl-Piezo1-/- mice. Our study elucidates the mechanism by which Piezo1 in gastric ghrelin cells regulate hepatic lipid accumulation, providing insights into potential treatments for fatty liver.

Piezo1-mediated mechanotransduction enhances macrophage oxidized low-density lipoprotein uptake and atherogenesis.

Macrophages in the vascular wall ingest and clear lipids, but abundant lipid accumulation leads to foam cell formation and atherosclerosis, a pathological condition often characterized by tissue stiffening. While the role of biochemical stimuli in the modulation of macrophage function is well studied, the role of biophysical cues and the molecules involved in mechanosensation are less well understood. Here, we use genetic and pharmacological tools to show extracellular oxidized low-density lipoproteins (oxLDLs) stimulate Ca2+ signaling through activation of the mechanically gated ion channel Piezo1. Moreover, macrophage Piezo1 expression is critical in the transduction of environmental stiffness and channel deletion suppresses, whereas a gain-of-function mutation exacerbates oxLDL uptake. Additionally, we find that depletion of myeloid Piezo1 protects from atherosclerotic plaque formation in vivo. Together, our study highlights an important role for Piezo1 and its respective mutations in macrophage mechanosensing, lipid uptake, and cardiovascular disease.

Chemical mapping of the surface interactome of PIEZO1 identifies CADM1 as a modulator of channel inactivation

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 touch through mechanoreceptors in 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 indicates 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.

High-frequency MHz-order vibration enables cell membrane remodeling and lipid microdomain manipulation

We elucidate the mechanism underpinning a recently discovered phenomenon in which cells respond to MHz-order mechanostimuli. Deformations induced along the plasma membrane under these external mechanical cues are observed to decrease the membrane tension, which, in turn, drives transient and reversible remodeling of its lipid structure. In particular, the increase and consequent coalescence of ordered lipid microdomains leads to closer proximity to mechanosensitive ion channels—Piezo1, in particular—that, due to crowding, results in their activation to mobilize influx of calcium (Ca2+) ions into the cell. It is the modulation of this second messenger that is responsible for the downstream signaling and cell fates that ensue. In addition, we show that such spatiotemporal control over the membrane microdomains in cells—without necessitating biochemical factors—facilitates aggregation and association of intrinsically disordered tau proteins in neuroblastoma cells, and their transformation to pathological conditions implicated in neurodegenerative diseases, thereby paving the way for the development of therapeutic intervention strategies.