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      Red Blood Cells: Chasing Interactions

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          Abstract

          Human red blood cells (RBC) are highly differentiated cells that have lost all organelles and most intracellular machineries during their maturation process. RBC are fundamental for the nearly all basic physiologic dynamics and they are key cells in the body’s respiratory system by being responsible for the oxygen transport to all cells and tissues, and delivery of carbon dioxide to the lungs. With their flexible structure RBC are capable to deform in order to travel through all blood vessels including very small capillaries. Throughout their in average 120 days lifespan, human RBC travel in the bloodstream and come in contact with a broad range of different cell types. In fact, RBC are able to interact and communicate with endothelial cells (ECs), platelets, macrophages, and bacteria. Additionally, they are involved in the maintenance of thrombosis and hemostasis and play an important role in the immune response against pathogens. To clarify the mechanisms of interaction of RBC and these other cells both in health and disease as well as to highlight the role of important key players, we focused our interest on RBC membrane components such as ion channels, proteins, and phospholipids.

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          The structure and function of the endothelial glycocalyx layer.

          Over the past decade, since it was first observed in vivo, there has been an explosion in interest in the thin (approximately 500 nm), gel-like endothelial glycocalyx layer (EGL) that coats the luminal surface of blood vessels. In this review, we examine the mechanical and biochemical properties of the EGL and the latest studies on the interactions of this layer with red and white blood cells. This includes its deformation owing to fluid shear stress, its penetration by leukocyte microvilli, and its restorative response after the passage of a white cell in a tightly fitting capillary. We also examine recently discovered functions of the EGL in modulating the oncotic forces that regulate the exchange of water in microvessels and the role of the EGL in transducing fluid shear stress into the intracellular cytoskeleton of endothelial cells, in the initiation of intracellular signaling, and in the inflammatory response.
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            Red cell membrane: past, present, and future.

            As a result of natural selection driven by severe forms of malaria, 1 in 6 humans in the world, more than 1 billion people, are affected by red cell abnormalities, making them the most common of the inherited disorders. The non-nucleated red cell is unique among human cell type in that the plasma membrane, its only structural component, accounts for all of its diverse antigenic, transport, and mechanical characteristics. Our current concept of the red cell membrane envisions it as a composite structure in which a membrane envelope composed of cholesterol and phospholipids is secured to an elastic network of skeletal proteins via transmembrane proteins. Structural and functional characterization of the many constituents of the red cell membrane, in conjunction with biophysical and physiologic studies, has led to detailed description of the way in which the remarkable mechanical properties and other important characteristics of the red cells arise, and of the manner in which they fail in disease states. Current studies in this very active and exciting field are continuing to produce new and unexpected revelations on the function of the red cell membrane and thus of the cell in health and disease, and shed new light on membrane function in other diverse cell types.
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              Piezo1 links mechanical forces to red blood cell volume

              Red blood cells (RBCs) experience significant mechanical forces while recirculating, but the consequences of these forces are not fully understood. Recent work has shown that gain-of-function mutations in mechanically activated Piezo1 cation channels are associated with the dehydrating RBC disease xerocytosis, implicating a role of mechanotransduction in RBC volume regulation. However, the mechanisms by which these mutations result in RBC dehydration are unknown. In this study, we show that RBCs exhibit robust calcium entry in response to mechanical stretch and that this entry is dependent on Piezo1 expression. Furthermore, RBCs from blood-cell-specific Piezo1 conditional knockout mice are overhydrated and exhibit increased fragility both in vitro and in vivo. Finally, we show that Yoda1, a chemical activator of Piezo1, causes calcium influx and subsequent dehydration of RBCs via downstream activation of the KCa3.1 Gardos channel, directly implicating Piezo1 signaling in RBC volume control. Therefore, mechanically activated Piezo1 plays an essential role in RBC volume homeostasis. DOI: http://dx.doi.org/10.7554/eLife.07370.001
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                Author and article information

                Contributors
                Journal
                Front Physiol
                Front Physiol
                Front. Physiol.
                Frontiers in Physiology
                Frontiers Media S.A.
                1664-042X
                31 July 2019
                2019
                : 10
                : 945
                Affiliations
                [1] 1Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht University , Utrecht, Netherlands
                [2] 2Theoretical Medicine and Biosciences, Saarland University , Homburg, Germany
                [3] 3Department of Laboratory of Translational Immunology and Department of Pediatric Immunology, Wilhelmina Children’s Hospital, University Medical Centre Utrecht , Utrecht, Netherlands
                [4] 4Experimental Physics, Saarland University , Saarbrücken, Germany
                [5] 5Department of Pharmaceutics, Utrecht Institute of Pharmaceutical Sciences (UIPS), Faculty of Science, Utrecht University , Utrecht, Netherlands
                [6] 6Paediatric Haematology Department, Wilhelmina Children’s Hospital, University Medical Centre Utrecht , Utrecht, Netherlands
                Author notes

                Edited by: Giampaolo Minetti, University of Pavia, Italy

                Reviewed by: Robert Campbell, The University of Utah, United States; Gregory Barshtein, Hebrew University of Jerusalem, Israel

                *Correspondence: Virginia Pretini, V.Pretini-2@ 123456umcutrecht.nl

                This article was submitted to Red Blood Cell Physiology, a section of the journal Frontiers in Physiology

                Article
                10.3389/fphys.2019.00945
                6684843
                30723415
                16467060-4a41-4bb8-adc7-a0ed87ed70b5
                Copyright © 2019 Pretini, Koenen, Kaestner, Fens, Schiffelers, Bartels and Van Wijk.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 09 May 2019
                : 09 July 2019
                Page count
                Figures: 3, Tables: 0, Equations: 0, References: 227, Pages: 17, Words: 0
                Categories
                Physiology
                Review

                Anatomy & Physiology
                red blood cells,interactions,membrane proteins,phospholipids,plasma proteins,platelets,endothelial cells,pathogens

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