Mechanical Stiffness Controls Dendritic Cell Metabolism and Function

Cell Reports, Journal Year: 2021, Volume and Issue: 34(2), P. 108609 - 108609

Published: Jan. 1, 2021

Stiffness in the tissue microenvironment changes most diseases and immunological conditions, but its direct influence on immune system is poorly understood. Here, we show that static tension impacts cell function, maturation, metabolism. Bone-marrow-derived and/or splenic dendritic cells (DCs) grown vitro at physiological resting stiffness have reduced proliferation, activation, cytokine production compared with under higher stiffness, mimicking fibro-inflammatory disease. Consistently, DCs increased activation flux of major glucose metabolic pathways. In DC models autoimmune diabetes tumor immunotherapy, primes to elicit an adaptive response. Mechanistic workup identifies Hippo-signaling molecule, TAZ, as well Ca2+-related ion channels, including potentially PIEZO1, important effectors impacting metabolism function tension. Tension also directs phenotypes monocyte-derived humans. Thus, mechanical a critical environmental cue innate immunity.

Language: Английский

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Structure, kinetic properties and biological function of mechanosensitive Piezo channels

Cell & Bioscience, Journal Year: 2021, Volume and Issue: 11(1)

Published: Jan. 9, 2021

Abstract Mechanotransduction couples mechanical stimulation with ion flux, which is critical for normal biological processes involved in neuronal cell development, pain sensation, and red blood volume regulation. Although they are key mechanotransducers, mechanosensitive channels mammals have remained difficult to identify. In 2010, Coste colleagues revealed a novel family of mechanically activated cation eukaryotes, consisting Piezo1 Piezo2 channels. These been proposed as the long-sought-after mammals. exhibit unique propeller-shaped architecture implicated mechanotransduction various processes, including touch balance, cardiovascular Furthermore, several mutations Piezo shown cause multiple hereditary human disorders, such autosomal recessive congenital lymphatic dysplasia. Notably, that dehydrated xerocytosis alter rate channel inactivation, indicating role their kinetics physiology. Given importance understanding process, this review focuses on structural details, kinetic properties potential function mechanosensors. We also briefly diseases caused by genes, these proteins.

Language: Английский

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Tethering Piezo channels to the actin cytoskeleton for mechanogating via the cadherin-β-catenin mechanotransduction complex

Cell Reports, Journal Year: 2022, Volume and Issue: 38(6), P. 110342 - 110342

Published: Feb. 1, 2022

The mechanically activated Piezo channel plays a versatile role in conferring mechanosensitivity to various cell types. However, how it incorporates its intrinsic and cellular components effectively sense long-range mechanical perturbation across remains elusive. Here we show that channels are biochemically functionally tethered the actin cytoskeleton via cadherin-β-catenin mechanotransduction complex, whose significantly impairs Piezo-mediated responses. Mechanistically, adhesive extracellular domain of E-cadherin interacts with cap Piezo1, which controls transmembrane gate, while cytosolic tail might interact domains close proximity intracellular gates, allowing direct focus adhesion-cytoskeleton-transmitted force for gating. Specific disruption intermolecular interactions prevents cytoskeleton-dependent gating Piezo1. Thus, propose force-from-filament model complement previously suggested force-from-lipids mechanogating channels, enabling them serve as tunable mechanotransducers.

Language: Английский

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The Importance of Mechanical Forces for in vitro Endothelial Cell Biology

Frontiers in Physiology, Journal Year: 2020, Volume and Issue: 11

Published: June 18, 2020

Blood and lymphatic vessels are lined by endothelial cells which constantly interact with their luminal abluminal extracellular environments. These interactions confer physical forces on the endothelium, such as shear stress, stretch stiffness, to mediate biological responses. often altered during disease, driving abnormal cell behaviour pathology. Therefore, it is critical that we understand mechanisms respond forces. Traditionally, in culture grown absence of flow stiff substrates plastic or glass. not subjected endure vivo, thus results these experiments do mimic those observed body. The field vascular biology now realise an intricate analysis signalling requires complex vitro systems vivo conditions. Here, will review what known about mechanical guide then discuss advancements models designed better microenvironment. A wider application technologies provide more biologically relevant information from cultured be reproducible conditions found

Language: Английский

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Mechanically activated piezo channels modulate outflow tract valve development through the Yap1 and Klf2-Notch signaling axis

eLife, Journal Year: 2019, Volume and Issue: 8

Published: Sept. 16, 2019

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

Language: Английский

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Understanding Chronic Venous Disease: A Critical Overview of Its Pathophysiology and Medical Management

Journal of Clinical Medicine, Journal Year: 2021, Volume and Issue: 10(15), P. 3239 - 3239

Published: July 22, 2021

Chronic venous disease (CVD) is a multifactorial condition affecting an important percentage of the global population. It ranges from mild clinical signs, such as telangiectasias or reticular veins, to severe manifestations, ulcerations. However, varicose veins (VVs) are most common manifestation CVD. The explicit mechanisms not well-understood. seems that genetics and plethora environmental agents play role in development progression exposure these factors leads altered hemodynamics system, described ambulatory hypertension, therefore promoting microcirculatory changes, inflammatory responses, hypoxia, wall remodeling, epigenetic variations, even with systemic implications. Thus, proper management patients CVD essential prevent potential harms disease, which also entails significant loss quality life individuals. Hence, aim present review collect current knowledge CVD, including its epidemiology, etiology, risk factors, but emphasizing pathophysiology medical care patients, diagnosis, treatments. Furthermore, future directions will be covered this work order provide fields explore context

Language: Английский

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Roles of mechanosensitive channel Piezo1/2 proteins in skeleton and other tissues

Bone Research, Journal Year: 2021, Volume and Issue: 9(1)

Published: Oct. 20, 2021

Mechanotransduction is a fundamental ability that allows living organisms to receive and respond physical signals from both the external internal environments. The mechanotransduction process requires range of special proteins termed mechanotransducers convert mechanical forces into biochemical in cells. Piezo are mechanically activated nonselective cation channels largest plasma membrane ion reported thus far. regulation two family members, Piezo1 Piezo2, has been have essential functions mechanosensation transduction different organs tissues. Recently, predominant contributions were occur skeletal system, especially bone development mechano-stimulated homeostasis. Here we review current studies focused on tissue-specific Piezo2 various backgrounds with highlights their importance regulating cell mechanotransduction. In this review, emphasize diverse related signaling pathways osteoblast lineage cells chondrocytes. We also summarize our understanding channel structures key findings about PIEZO gene mutations human diseases.

Language: Английский

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Structural Designs and Mechanogating Mechanisms of the Mechanosensitive Piezo Channels

Trends in Biochemical Sciences, Journal Year: 2021, Volume and Issue: 46(6), P. 472 - 488

Published: Feb. 18, 2021

Language: Английский

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Vascular mechanotransduction

Physiological Reviews, Journal Year: 2023, Volume and Issue: 103(2), P. 1247 - 1421

Published: Jan. 5, 2023

This review aims to survey the current state of mechanotransduction in vascular smooth muscle cells (VSMCs) and endothelial (ECs), including their sensing mechanical stimuli transduction signals that result acute functional modulation longer-term transcriptomic epigenetic regulation blood vessels. The mechanosensors discussed include ion channels, plasma membrane-associated structures receptors, junction proteins. mechanosignaling pathways presented cytoskeleton, integrins, extracellular matrix, intracellular signaling molecules. These are followed by discussions on transcriptome epigenetics, relevance health disease, interactions between VSMCs ECs. Throughout this review, we offer suggestions for specific topics require further understanding. In closing section conclusions perspectives, summarize what is known point out need treat vasculature as a system, not only ECs but also matrix other types such resident macrophages pericytes, so can fully understand physiology pathophysiology vessel whole, thus enhancing comprehension, diagnosis, treatment, prevention diseases.

Language: Английский

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Spatiotemporal dynamics of PIEZO1 localization controls keratinocyte migration during wound healing

eLife, Journal Year: 2021, Volume and Issue: 10

Published: Sept. 27, 2021

Keratinocytes, the predominant cell type of epidermis, migrate to reinstate epithelial barrier during wound healing. Mechanical cues are known regulate keratinocyte re-epithelialization and healing; however, underlying molecular transducers biophysical mechanisms remain elusive. Here, we show through molecular, cellular, organismal studies that mechanically activated ion channel PIEZO1 regulates migration Epidermal-specific Piezo1 knockout mice exhibited faster closure while gain-of-function displayed slower compared littermate controls. By imaging spatiotemporal localization dynamics endogenous channels, find enrichment at some regions edge induces a localized cellular retraction slows collective migration. In migrating single keratinocytes, is enriched rear cell, where maximal occurs, chemical activation enhances as well Our findings uncover novel may suggest potential pharmacological target for treatment. More broadly, nanoscale channels can control tissue-scale events, finding with implications beyond healing processes diverse development, homeostasis, disease, repair.

Language: Английский

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