Mechanically activated ion channel PIEZO1 is required for lymphatic valve formation

Nonomura, Kazuteru; Lukacs, Viktor; Sweet, Daniel T.; Goddard, Lauren M.; Akemi, Kanie; Whitwam, Tess; Ranade, Sanjeev S.; Fujimori, Toshihiko; Kahn, Mark L.; Patapoutian, Ardem

doi:10.1073/pnas.1817070115

Cited by 209 publications

(217 citation statements)

References 47 publications

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“…Despite these significant advancements, a challenge toward a more complete understanding of the mechanisms of force‐sensing in LECs is that OSS often regulates molecules that also have flow‐independent roles . However, recently the mechanically activated cation channel PIEZO1 was shown to be required for lymphatic valve formation, thereby identifying a putative mechanosensor that may be targeted to help enhance lymphatic valve regeneration.…”

Section: Lymphatic Vessel Physiology Function and Lymphangiogenesismentioning

confidence: 99%

“…Despite these significant advancements, a challenge toward a more complete understanding of the mechanisms of force-sensing in LECs is that OSS often regulates molecules that also have flowindependent roles. 70 However, recently the mechanically activated cation channel PIEZO1 76 was shown to be required for lymphatic valve formation, 77 thereby identifying a putative mechanosensor that may be targeted to help enhance lymphatic valve regeneration. Although there is a wealth of evidence that fluid forces affect LEC phenotype, to our knowledge, no study has simultaneously examined the interplay of interstitial flow, luminal shear, and cyclic strain in mediating lymphangiogenesis from an intact vessel with facile experimental manipulation.…”

Section: Lymphatic Vessel Mechanobiologymentioning

confidence: 99%

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Application of microscale culture technologies for studying lymphatic vessel biology

2019

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Immense progress in microscale engineering technologies has significantly expanded the capabilities of in vitro cell culture systems for reconstituting physiological microenvironments that are mediated by biomolecular gradients, fluid transport, and mechanical forces. Here, we examine the innovative approaches based on microfabricated vessels for studying lymphatic biology. To help understand the necessary design requirements for microfluidic models, we first summarize lymphatic vessel structure and function. Next, we provide an overview of the molecular and biomechanical mediators of lymphatic vessel function. Then we discuss the past achievements and new opportunities for microfluidic culture models to a broad range of applications pertaining to lymphatic vessel physiology. We emphasize the unique attributes of microfluidic systems that enable the recapitulation of multiple physicochemical cues in vitro for studying lymphatic pathophysiology. Current challenges and future outlooks of microscale technology for studying lymphatics are also discussed. Collectively, we make the assertion that further progress in the development of microscale models will continue to enrich our mechanistic understanding of lymphatic biology and physiology to help realize the promise of the lymphatic vasculature as a therapeutic target for a broad spectrum of diseases.

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Section: Lymphatic Vessel Physiology Function and Lymphangiogenesismentioning

confidence: 99%

Section: Lymphatic Vessel Mechanobiologymentioning

confidence: 99%

Application of microscale culture technologies for studying lymphatic vessel biology

2019

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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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“…It will be interesting to see if these functions also rely on the modulation of the expression of ECM proteins by the Piezo-Yap1 axis in angiogenic contexts. Similarly, the downstream targets of piezo are not identified in the lymphatic valves and a number of flow responsive transcription factors such as foxc2 and Nfat1 (Sabine et al, 2012;Sabine et al, 2015;Sweet et al, 2015) are normally expressed of piezo mutants (Nonomura et al, 2018).…”

Section: Yap1 and Hippo Pathways Are Regulators Of The Oft Valve Formmentioning

confidence: 99%

Mechanically activated Piezo channels control outflow tract valve development through Yap1 and Klf2-Notch signaling axis

Duchemin

Vignes

Vermot

2019

Preprint

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Mechanical forces are well known for modulating heart valve developmental programs. Yet, it is still unclear how genetic programs and mechanosensation interact during heart valve development. Here, we assessed the mechanosensitive pathways involved during zebrafish outflow tract (OFT) valve development in vivo. Our results show that the hippo effector Yap1, Klf2, and the Notch signaling pathway are all essential for OFT valve morphogenesis in response to mechanical forces, albeit active in different cell layers. Furthermore, we show that Piezo and TRP mechanosensitive channels are essential for regulating these pathways. In addition, live reporters reveal that piezo controls Klf2 and Notch activity in the endothelium and Yap1 expression in the smooth muscle progenitors to coordinate OFT valve morphogenesis. Together, this work identifies a unique morphogenetic program during OFT valve formation and places Piezo as a central modulator of the cell response to forces in this process.

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Mechanically activated ion channel PIEZO1 is required for lymphatic valve formation

Cited by 209 publications

References 47 publications

Application of microscale culture technologies for studying lymphatic vessel biology

Application of microscale culture technologies for studying lymphatic vessel biology

Piezo1 channel activates ADAM10 sheddase to regulate Notch1 and gene expression

Mechanically activated Piezo channels control outflow tract valve development through Yap1 and Klf2-Notch signaling axis

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