The ion channels Piezo1 and TRPV4 have both, independently, been implicated in high venous pressure– and fluid shear stress–induced vascular hyperpermeability in endothelial cells. However, the ...mechanism by which Piezo1 and TRPV4 channels execute the same function is poorly understood. Here we demonstrate that Piezo1 regulates TRPV4 channel activation in endothelial cells and that Piezo1-mediated TRPV4 channel opening is a function of the strength and duration of fluid shear stress. We first confirmed that either fluid shear stress or the Piezo1 agonist, Yoda1, led to an elevation in intracellular calcium (Ca2+i) and that application of the Piezo1 antagonist, GsMTx4, completely blocked this change. We discovered that high and prolonged shear stress caused sustained Ca2+i elevation that was blocked by inhibition of TRPV4 channel opening. Moreover, Piezo1 stimulated TRPV4 opening through activation of phospholipase A2. TRPV4-dependent sustained Ca2+i elevation was responsible for fluid shear stress–mediated and Piezo1-mediated disruption of adherens junctions and actin remodeling. Blockade of TRPV4 channels with the selective TRPV4 blocker, HC067047, prevented the loss of endothelial cell integrity and actin disruption induced by Yoda1 or shear stress and prevented Piezo1-induced monocyte adhesion to endothelial cell monolayers. These findings demonstrate that Piezo1 activation by fluid shear stress initiates a calcium signal that causes TRPV4 opening, which in turn is responsible for the sustained phase calcium elevation that triggers pathological events in endothelial cells. Thus, deleterious effects of shear stress are initiated by Piezo1 but require TRPV4.
Visceral pain associated with irritable bowel syndrome afflicts 15% of the US population. Although treatments are limited, guanylyl cyclase C (GUCY2C) agonists alleviate pain and constipation. Until ...now, it was assumed that the activation of GUCY2C and production of cGMP in enterocytes stimulated fluid secretion and reduced visceral sensation. The recent discovery that a subtype of enteroendocrine cells (EECs) known as neuropod cells synapse with submucosal neurons unveiled a pathway for communicating gut signals to the nervous system. In this issue of the JCI, Barton et al. report that GUCY2C is enriched in neuropod cells and is involved with sensory nerve firing. Selective deletion of GUCY2C in mouse models suggests that defective GUCY2C neuropod-cell signaling underlies visceral pain. These studies introduce possibilities for dissociating the secretory and analgesic effects of GUCY2C agonism. Although further work remains, unveiling the role of neuropod cells is a major step in understanding visceral pain.
There is a large amount of evidence available about the relative merits of unicompartmental and total knee arthroplasty (UKA and TKA). Based on the same evidence, different people draw different ...conclusions and as a result, there is great variability in the usage of UKA. The revision rate of UKA is much higher than TKA and so some surgeons conclude that UKA should not be performed. Other surgeons believe that the main reason for the high revision rate is that UKA is easy to revise and, therefore, the threshold for revision is low. They also believe that UKA has many advantages over TKA such as a faster recovery, lower morbidity and mortality and better function. They therefore conclude that UKA should be undertaken whenever appropriate. The solution to this argument is to minimise the revision rate of UKA, thereby addressing the main disadvantage of UKA. The evidence suggests that this will be achieved if surgeons use UKA for at least 20% of their knee arthroplasties and use implants that are appropriate for these broad indications.
Whether to use total or unicompartmental knee replacement (TKA/UKA) for end-stage knee osteoarthritis remains controversial. Although UKA results in a faster recovery, lower rates of morbidity and ...mortality and fewer complications, the long-term revision rate is substantially higher than that for TKA. The effect of each intervention on patient-reported outcome remains unclear. The aim of this study was to determine whether six-month patient-reported outcome measures (PROMs) are better in patients after TKA or UKA, using data from a large national joint registry (NJR). We carried out a propensity score-matched cohort study which compared six-month PROMs after TKA and UKA in patients enrolled in the NJR for England and Wales, and the English national PROM collection programme. A total of 3519 UKA patients were matched to 10 557 TKAs. The mean six-month PROMs favoured UKA: the Oxford Knee Score was 37.7 (95% confidence interval (CI) 37.4 to 38.0) for UKA and 36.1 (95% CI 35.9 to 36.3) for TKA; the mean EuroQol EQ-5D index was 0.772 (95% CI 0.764 to 0.780) for UKA and 0.751 (95% CI 0.747 to 0.756) for TKA. UKA patients were more likely to achieve excellent results (odds ratio (OR) 1.59, 95% CI 1.47 to 1.72, p < 0.001) and to be highly satisfied (OR 1.27, 95% CI 1.17 to 1.39, p < 0.001), and were less likely to report complications than those who had undergone TKA. UKA gives better early patient-reported outcomes than TKA; these differences are most marked for the very best outcomes. Complications and readmission are more likely after TKA. Although the data presented reflect the short-term outcome, they suggest that the high revision rate for UKA may not be because of poorer clinical outcomes. These factors should inform decision-making in patients eligible for either procedure.
Merely touching the pancreas can lead to premature zymogen activation and pancreatitis but the mechanism is not completely understood. Here we demonstrate that pancreatic acinar cells express the ...mechanoreceptor Piezo1 and application of pressure within the gland produces pancreatitis. To determine if this effect is through Piezo1 activation, we induce pancreatitis by intrapancreatic duct instillation of the Piezo1 agonist Yoda1. Pancreatitis induced by pressure within the gland is prevented by a Piezo1 antagonist. In pancreatic acinar cells, Yoda1 stimulates calcium influx and induces calcium-dependent pancreatic injury. Finally, selective acinar cell-specific genetic deletion of Piezo1 protects mice against pressure-induced pancreatitis. Thus, activation of Piezo1 in pancreatic acinar cells is a mechanism for pancreatitis and may explain why pancreatitis develops following pressure on the gland as in abdominal trauma, pancreatic duct obstruction, pancreatography, or pancreatic surgery. Piezo1 blockade may prevent pancreatitis when manipulation of the gland is anticipated.
All cells in the body are exposed to physical force in the form of tension, compression, gravity, shear stress, or pressure. Cells convert these mechanical cues into intracellular biochemical ...signals; this process is an inherent property of all cells and is essential for numerous cellular functions. A cell's ability to respond to force largely depends on the array of mechanical ion channels expressed on the cell surface. Altered mechanosensing impairs conscious senses, such as touch and hearing, and unconscious senses, like blood pressure regulation and gastrointestinal (GI) activity. The GI tract's ability to sense pressure changes and mechanical force is essential for regulating motility, but it also underlies pain originating in the GI tract. Recent identification of the mechanically activated ion channels Piezo1 and Piezo2 in the gut and the effects of abnormal ion channel regulation on cellular function indicate that these channels may play a pathogenic role in disease. Here, we discuss our current understanding of mechanically activated Piezo channels in the pathogenesis of pancreatic and GI diseases, including pancreatitis, diabetes mellitus, irritable bowel syndrome, GI tumors, and inflammatory bowel disease. We also describe how Piezo channels could be important targets for treating GI diseases.
The enteroendocrine cell is the cornerstone of gastrointestinal chemosensation. In the intestine and colon, this cell is stimulated by nutrients, tastants that elicit the perception of flavor, and ...bacterial by-products; and in response, the cell secretes hormones like cholecystokinin and peptide YY--both potent regulators of appetite. The development of transgenic mice with enteroendocrine cells expressing green fluorescent protein has allowed for the elucidation of the apical nutrient sensing mechanisms of the cell. However, the basal secretory aspects of the enteroendocrine cell remain largely unexplored, particularly because a complete account of the enteroendocrine cell ultrastructure does not exist. Today, the fine ultrastructure of a specific cell can be revealed in the third dimension thanks to the invention of serial block face scanning electron microscopy (SBEM). Here, we bridged confocal microscopy with SBEM to identify the enteroendocrine cell of the mouse and study its ultrastructure in the third dimension. The results demonstrated that 73.5% of the peptide-secreting vesicles in the enteroendocrine cell are contained within an axon-like basal process. We called this process a neuropod. This neuropod contains neurofilaments, which are typical structural proteins of axons. Surprisingly, the SBEM data also demonstrated that the enteroendocrine cell neuropod is escorted by enteric glia--the cells that nurture enteric neurons. We extended these structural findings into an in vitro intestinal organoid system, in which the addition of glial derived neurotrophic factors enhanced the development of neuropods in enteroendocrine cells. These findings open a new avenue of exploration in gastrointestinal chemosensation by unveiling an unforeseen physical relationship between enteric glia and enteroendocrine cells.
A path for α-synuclein from the gut to the nervous system. Enteroendocrine cells (EECs) express α-synuclein and connect to α-synuclein-containing enteric nerves. This circuit provides a possible ...route for bacteria or toxins in the gut to induce abnormal α-synuclein formation that could transfer to the nervous system to initiate Parkinson’s disease.
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•Parkinson’s disease is characterized by Lewy bodies in the brain and peripheral nerves.•Misfolding and aggregation of α-synuclein leads to Lewy body formation.•Misfolded α-synuclein can spread in a prion-like fashion.•Epidemiological and experimental evidence suggest PD arises in the gut.•Like neurons, enteroendocrine cells express α-synuclein and could be a source of PD.
Parkinson’s disease (PD) is a debilitating neurodegenerative condition associated with tremor, rigidity, dementia, and gastrointestinal symptoms such as constipation, nausea and vomiting. The pathological hallmarks of PD are Lewy bodies and neurites in the brain and peripheral nerves. The major constituent of Lewy bodies is the neuronal protein α-synuclein. Misfolding of α-synuclein confers prion-like properties enabling its spread from cell to cell. Misfolded α-synuclein also serves as a template and induces misfolding of endogenous α-synuclein in recipient cells leading to the formation of oligomers that progress to fibrils and eventually Lewy bodies. Accumulating evidence suggests that PD may arise in the gut. Clinically, gastrointestinal symptoms often appear in patients before other neurological signs and aggregates of α-synuclein have been found in enteric nerves of PD patients. Importantly, patients undergoing vagotomy have a reduced risk of developing PD. Experimentally, abnormal forms of α-synuclein appear in enteric nerves before they appear in the brain and injection of abnormal α-synuclein into the wall of the intestine spreads to the vagus nerve. Ingested toxins and alterations in gut microbiota can induce α-synuclein aggregation and PD, however, it is not known how PD starts. Recently, it has been shown that sensory cells of the gut known as enteroendocrine cells (EECs) contain α-synuclein and synapse with enteric nerves, thus providing a connection from the gut to the brain. It is possible that abnormal α-synuclein first develops in EECs and spreads to the nervous system.
Enteroendocrine cells (EECs) are specialized sensory cells in the intestinal epithelium that sense and transduce nutrient information. Consumption of dietary fat contributes to metabolic disorders, ...but EEC adaptations to high fat feeding were unknown. Here, we established a new experimental system to directly investigate EEC activity in vivo using a zebrafish reporter of EEC calcium signaling. Our results reveal that high fat feeding alters EEC morphology and converts them into a nutrient insensitive state that is coupled to endoplasmic reticulum (ER) stress. We called this novel adaptation 'EEC silencing'. Gnotobiotic studies revealed that germ-free zebrafish are resistant to high fat diet induced EEC silencing. High fat feeding altered gut microbiota composition including enrichment of
bacteria, and we identified an
strain sufficient to induce EEC silencing. These results establish a new mechanism by which dietary fat and gut microbiota modulate EEC nutrient sensing and signaling.
We present constraints on extensions of the minimal cosmological models dominated by dark matter and dark energy, ΛCDM and wCDM, by using a combined analysis of galaxy clustering and weak ...gravitational lensing from the first-year data of the Dark Energy Survey (DES Y1) in combination with external data. We consider four extensions of the minimal dark energy-dominated scenarios: (1) nonzero curvature Ωk, (2) number of relativistic species Neff different from the standard value of 3.046, (3) time-varying equation-of-state of dark energy described by the parameters w0 and wa (alternatively quoted by the values at the pivot redshift, wp, and wa), and (4) modified gravity described by the parameters μ0 and Σ0 that modify the metric potentials. We also consider external information from Planck cosmic microwave background measurements; baryon acoustic oscillation measurements from SDSS, 6dF, and BOSS; redshift-space distortion measurements from BOSS; and type Ia supernova information from the Pantheon compilation of datasets. Constraints on curvature and the number of relativistic species are dominated by the external data; when these are combined with DES Y1, we find Ωk=0.0020−0.0032+0.0037 at the 68% confidence level, and the upper limit Neff<3.28(3.55) at 68% (95%) confidence, assuming a hard prior Neff>3.0. For the time-varying equation-of-state, we find the pivot value (wp,wa)=(−0.91−0.23+0.19,−0.57−1.11+0.93) at pivot redshift zp=0.27 from DES alone, and (wp,wa)=(−1.01−0.04+0.04,−0.28−0.48+0.37) at zp=0.20 from DES Y1 combined with external data; in either case we find no evidence for the temporal variation of the equation of state. For modified gravity, we find the present-day value of the relevant parameters to be Σ0=0.43−0.29+0.28 from DES Y1 alone, and (Σ0,μ0)=(0.06−0.07+0.08,−0.11−0.46+0.42) from DES Y1 combined with external data. These modified-gravity constraints are consistent with predictions from general relativity.
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