Mechanotransduction mechanisms in human erythrocytes: Fundamental physiology and clinical significance.

The hallmarks of mechanosensitive ion channels have been observed for half a century in various cell lines, although their mechanisms and molecular identities remained unknown until recently. Identification of the bona fide mammalian mechanosensory Piezo channels resulted in an explosion of research exploring the translation of mechanical cues into biochemical signals and dynamic cell morphology responses. One of the Piezo isoforms - Piezo1 - is integral in the erythrocyte (red blood cell; RBC) membrane. The exceptional flexibility of RBCs and the absence of intracellular organelles provides a unique mechanical and biochemical environment dictating specific Piezo1-functionality. The Piezo1-endowed capacity of RBCs to sense the mechanical forces acting upon them during their continuous traversal of the circulatory system has solidified a brewing step-change in our fundamental understanding of RBC biology in health and disease; that is, RBCs are not biologically inert but rather capable of complex dynamic cellular signaling. Although several lines of investigation have unearthed various regulatory mechanisms of signaling pathway activation by RBC-Piezo1, these independent studies have not yet been synthesized into a cohesive picture. The aim of the present review is to thus summarize the progress in elucidating how Piezo1 functions in the unique cellular environment of RBCs, challenge classical views of this enucleated cell, and provoke developments for future work.