To deform or not to deform: the evolutionary basis of mammalian red blood cell deformability

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Red blood cells (RBCs) are highly deformable cells that undergo dramatic shape changes in both physiological and pathological settings. While in circulation, RBCs deform from their native biconcave shape into a bullet-like shape to fit through the capillaries. The fact that this shape change occurs while maintaining a constant surface area is fundamental for the delivery of oxygen to the body. The deformability of RBCs is determined by the composition of the cytoskeleton, the lipid bilayer membrane, and the viscosity of the cytoplasm (1). In this issue of the Biophysical Journal, Hale et al. examine the evolution of the cytoskeletal protein, spectrin, in determining membrane properties and allowing for effective tissue oxygenation (2).

Structurally, RBCs are made up of a triangular network of α- and β-spectrin that is tethered to the lipid bilayer by a series of proteins. RBCs maintain their biconcave shape because of the inherent tension of the spectrin network (3). Spectrin forms tetramers due to the association of αβ dimers. There are two isoforms of spectrin, the erythroid isoform (I) and the nonerythroid isoform (II) (4). It is known that the αII-βII tetramers are more stable than their erythroid counterpart because of the strength of self-association between dimers (5). However, the physiological implications of differences in strength of dimer self-association remain relatively unexplored. Understanding the cellular mechanisms that facilitate RBC functionality is fundamental for the development of treatments when RBC deformability is decreased, such as occurs in patients with diabetes, smokers, people with high cholesterol, and those with sickle cell disease (6).

Hale et al. explored the biophysical interactions between the binding strength of αβ dimers and the deformability of RBCs. Interestingly, they note that birds and reptiles do not encode for αI spectrin in their RBCs and only have the nonerythroid isoform (αII). This poses the question of the evolutionary basis for why humans have the αI isoform of spectrin in their RBCs. To shed light on the evolutionary basis of erythroid spectrin in mammals, there was a need to determine the role that αI versus αII spectrin has on RBC functionality. To address this need, Hale et al. developed an αIIβI knockin murine model that encoded for an αII binding site on βI spectrin. It is believed that the self-association of the cytoskeleton governs the deformation of RBCs under shear forces (7), such as occur during the oxygenation/deoxygenation process. However, mechanistically it was previously unknown how RBCs achieved this degree of deformability. Hale et al. show using ektacytometry that αIIβI knockin mice have less deformable RBCs under the application of shear forces (Fig. 1). αII spectrin leads to increased connectivity of the cytoskeleton network to the cell membrane through membrane proteins, which manifests in the reduction in bulk deformability.

Figure 1.

Influences of α-spectrin isoform on the deformability of RBCs in Hale et al. (2). Left: represents a control red blood cell with αI isoform of spectrin that deforms under shear. Right: represents a red blood cell with αIIβI tetramers that show increased connectivity to the cellular membrane through membrane proteins and a reduced cellular deformability under shear stress. To see this figure in color, go online.

From an evolutionary standpoint, Hale et al. show that αI spectrin provides RBCs the ability to deform through the capillary system, making the oxygenation/deoxygenation process more efficient. However, the question remains whether this change imparts any pathological consequences. Birds and reptiles do not develop occlusive thrombi such as those that lead to heart attacks and strokes in mammals (8). Paradoxically, many conditions with decreased RBC deformability, such as sickle cell disease, are linked to an increased risk for thrombotic events that can lead to heart attacks and strokes (9). During the blood clotting/contraction process, RBCs are compacted, which leads to shape change from biconcave to a tessellated network of polyhedral shape cells termed polyhedrocytes (10,11). Increased rigidity of RBCs, such as occurs in sickle cell disease, leads to impaired compaction of RBCs and reduced polyhedrocyte formation (12). The question of the influence of the spectrin isoform on the deformability in response to compressive forces, such as would occur during clot contraction, remains unanswered and could have important clinical implications. By understanding the biophysical mechanism governing the deformability of RBCs, there is the potential to develop novel treatments for conditions in which RBCs are less deformable, such as sickle cell disease.

Editor: Vivek Shenoy.