Mechanotransduction mechanisms in human erythrocytes: Fundamental physiology and clinical significance

Abstract

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.

Keywords: Mechanotransduction; Piezo1; biophysics; blood; membrane; red blood cell.

Figure 1.

The physical properties of red blood cells (RBC) influence their position in flow and govern interactions with the vascular wall through facilitating a cell-poor region. The cell-poor region, and the associated moderate shear stresses within larger vessels, may dampen membrane strain and thus Piezo1 activation in health, but it is clear that the higher shear regions of resistance vessels are sufficient to alter the morphology of RBC, and the corresponding membrane strain activates a proportion of the Piezo1 pool (active Piezo1 represented by dark blue and “larger” channels for illustrative purposes only).

Figure 2.

Red blood cells (RBC) provide a unique physical environment for Piezo1-dependent mechanosensing due to exceptional cellular flexibility and morphological geometry with complex curvatures. Membrane lipids and cytoskeletal elements likely contribute to dynamic channel gating during cellular deformation. Potential Piezo1-interacting proteins are indicated as “unidentified intracellular proteins.” Cellular (e.g. intracellular protein organization), genetic (e.g. mutations in the PIEZO1-gene causing hereditary blood disorders), mechanical (e.g. heterogenous vessel geometry) and chemical (e.g. oxygen tensions) effectors encountered by RBC during transit of the vasculature modulate Piezo1-gating, although the underlying mechanism are poorly understood.