Piezo1 links mechanical forces to red blood cell volume.

Stuart M Cahalan,Sanjeev S Ranade,Michael Bandell,Shu Chien,Ardem Patapoutian,Viktor Lukacs

doi:10.7554/elife.07370

Abstract

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.

Highlights

Mammalian red blood cells (RBCs) are rather unique in that they lack a nucleus and many organelles and that they traverse the circulatory system several hundred thousand times in their life cycle
The potential role of Piezo1 in Red blood cells (RBCs) physiology is most clearly demonstrated by many gain-of-function mutations in Piezo1 that have been identified in patients with the RBC disease xerocytosis, called dehydrated hereditary stomatocytosis (DHS)
Our findings suggest a link between mechanical forces and RBC volume via Ca2+ influx through Piezo1

Summary

Introduction

Mammalian red blood cells (RBCs) are rather unique in that they lack a nucleus and many organelles and that they traverse the circulatory system several hundred thousand times in their life cycle. RBCs experience significant mechanical forces while recirculating that influence their physiology in many ways, including changes in deformability (Chien, 1987), ATP release (Sprague et al, 2001), NO release (Yalcin et al, 2008), and Ca2+ influx (Larsen et al, 1981; Dyrda and et al, 2010), the latter of which can influence RBC volume. The potential role of Piezo in RBC physiology is most clearly demonstrated by many gain-of-function mutations in Piezo that have been identified in patients with the RBC disease xerocytosis, called dehydrated hereditary stomatocytosis (DHS)

Methods

Results

Conclusion