Piezo1 is a mechanically activated ion channel and mediates pressure induced pancreatitis

Romac, Joelle; Shahid, Rafiq A.; Swain, Sandip M.; Vigna, Steven R.; Liddle, Rodger A.

doi:10.1038/s41467-018-04194-9

Cited by 179 publications

(147 citation statements)

References 58 publications

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“…In non-neuronal tissue, PIEZO1 has been shown to regulate numerous physiological processes ranging from the maintenance of epithelial barrier integrity (24,26) to lymphatic valve development (27), red blood cell volume (28) and myotube formation (29). In the pancreas, PIEZO1 mediates pressure-induced pancreatitis (30), however, roles for PIEZO1 channels in other exocrine organs, including the mammary gland, remain unexplored. Here, we characterize the mammary force landscape and investigate roles for PIEZO1 channels in sensing and transducing epithelial cell forces to sustain or suspend lactation.…”

Section: Introductionmentioning

confidence: 99%

“…(60). All samples were obtained with informed consent and patients (female, aged[25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42] were recruited under a protocol approved by the Indiana University Institutional Review Board (IRB protocol number 1011003097) and according to The Code of Ethics of the World Medical Association (Declaration of Helsinki). The current project received additional, site-specific approval from the Mater Misericordiae Ltd Human Research Ethics Committee.…”

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confidence: 99%

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Mammary mechanobiology: mechanically-activated ion channels in lactation and involution

Stewart

Hughes

Stevenson

et al. 2019

Preprint

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A mother's ability to produce a nutritionally-complete neonatal food source has provided a powerful evolutionary advantage to mammals. Milk production by secretory mammary epithelial cells is adaptive, its release is exquisitely timed and its own glandular stagnation with the permanent cessation of suckling triggers the programmed cell death and tissue remodeling that enables female mammals to nurse successive progeny. Both chemical and mechanical signals control epithelial expansion, function and remodeling. Despite this duality of input, however, the nature and function of mechanical forces in the mammary gland remain unknown. Here, we characterize the mammary force landscape and the capacity of luminal and basal epithelial cells to Short title: The mechanics of milk production experience and exert force. We explore the molecular instruments for force-sensing in the mammary gland and the physiological requirement for PIEZO1 in lactation and involution. Our study supports the existence of a multifaceted system of chemical and mechanical sensing in the mammary gland, and a protective redundancy that ensures continued lactational competence and offspring survival.

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Section: Introductionmentioning

confidence: 99%

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confidence: 99%

Mammary mechanobiology: mechanically-activated ion channels in lactation and involution

Stewart

Hughes

Stevenson

et al. 2019

Preprint

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“…A prior report has suggested lack of specificity of Yoda1 for Piezo1 channels 40 but the GsMTx4 toxin used as the basis of this proposal has limited value as a tool for evaluating Piezo1. Other prior studies have shown that genetic deletion of Piezo1 abolishes Yoda1's effects 10,36,41,42 and that Piezo1 knockdown by RNA interference suppresses its effects 14,30,[43][44][45][46] , consistent with Yoda1 having only Piezo1-mediated effects. Specific structure-activity requirements of Yoda1 at Piezo1 have been observed 24 and it does not activate Piezo2 21 .…”

Section: Discussionmentioning

confidence: 52%

Piezo1 channel activates ADAM10 sheddase to regulate Notch1 and gene expression

Beech

Caolo

Debant

et al. 2019

Preprint

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Mechanical force has emerged as a determinant of Notch signalling but the mechanisms of force sensing and coupling to Notch are unclear. Here we propose a role for Piezo1 channels, the recently identified mechanosensors of mammalian systems. Piezo1 channel opening in response to shear stress or a chemical agonist led to activation of a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), a Ca 2+ -regulated transmembrane sheddase that mediates S2 Notch1 cleavage. Consistent with this observation there was increased Notch1 intracellular domain (NICD) that depended on ADAM10 and the downstream S3 cleavage enzyme, -secretase. Endothelial-specific disruption of Piezo1 in mice led to decreased Notch1-regulated gene expression in hepatic vasculature, consistent with prior evidence that Notch1 controls hepatic perfusion. The data suggest Piezo1 as a mechanism for coupling physiological force at the endothelium to ADAM10, Notch1, gene expression and vascular function.

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“…During forskolin stimulation the secreted fluid expands the lumen and the increasing intraluminal pressure prevents water efflux that might therefore not follow the ion current linearly. In addition, the increased tension might activate the mechanoreceptors (such as Piezo1) in the apical membrane of epithelial cells [40]. This shall not be a problem in samples with CFTR expression defects, where the initial fluid secretion is marginal [41].…”

Section: Discussionmentioning

confidence: 99%

Mouse pancreatic ductal organoid culture as a relevant model to study exocrine pancreatic ion secretion

Molnár

Madácsy

Varga

et al. 2020

Laboratory Investigation

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Pancreatic exocrine secretory processes are challenging to investigate on primary epithelial cells. Pancreatic organoid cultures may help to overcome shortcomings of the current models, however the ion secretory processes in pancreatic organoids-and therefore their physiological relevance or their utility in disease modeling-are not known. To answer these questions, we provide side-by-side comparison of gene expression, morphology, and function of epithelial cells in primary isolated pancreatic ducts and organoids. We used mouse pancreatic ductal fragments for experiments or were grown in Matrigel to obtain organoid cultures. Using PCR analysis we showed that gene expression of ion channels and transporters remarkably overlap in primary ductal cells and organoids. Morphological analysis with scanning electron microscopy revealed that pancreatic organoids form polarized monolayers with brush border on the apical membrane. Whereas the expression and localization of key proteins involved in ductal secretion (cystic fibrosis transmembrane conductance regulator, Na + /H + exchanger 1 and electrogenic Na + /HCO 3 − cotransporter 1) are equivalent to the primary ductal fragments.Measurements of intracellular pH and Cl − levels revealed no significant difference in the activities of the apical Cl − /HCO 3 − exchange, or in the basolateral Na + dependent HCO 3 − uptake. In summary we found that ion transport activities in the mouse pancreatic organoids are remarkably similar to those observed in freshly isolated primary ductal fragments. These results suggest that organoids can be suitable and robust model to study pancreatic ductal epithelial ion transport in health and diseases and facilitate drug development for secretory pancreatic disorders like cystic fibrosis, or chronic pancreatitis.

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Piezo1 is a mechanically activated ion channel and mediates pressure induced pancreatitis

Cited by 179 publications

References 58 publications

Mammary mechanobiology: mechanically-activated ion channels in lactation and involution

Mammary mechanobiology: mechanically-activated ion channels in lactation and involution

Piezo1 channel activates ADAM10 sheddase to regulate Notch1 and gene expression

Mouse pancreatic ductal organoid culture as a relevant model to study exocrine pancreatic ion secretion

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