Image-based model of the spectrin cytoskeleton for red blood cell simulation

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Abstract
We simulate deformable red blood cells in the microcirculation using the immersed boundary method with a cytoskeletal model that incorporates structural details revealed by tomographic images. The elasticity of red blood cells is known to be supplied by both their lipid bilayer membranes, which resist bending and local changes in area, and their cytoskeletons, which resist in-plane shear. The cytoskeleton consists of spectrin tetramers that are tethered to the lipid bilayer by ankyrin and by actin-based junctional complexes. We model the cytoskeleton as a random geometric graph, with nodes corresponding to junctional complexes and with edges corresponding to spectrin tetramers such that the edge lengths are given by the end-to-end distances between nodes. The statistical properties of this graph are based on distributions gathered from three-dimensional tomographic images of the cytoskeleton by a segmentation algorithm. We show that the elastic response of our model cytoskeleton, in which the spectrin polymers are treated as entropic springs, is in good agreement with the experimentally measured shear modulus. By simulating red blood cells in flow with the immersed boundary method, we compare this discrete cytoskeletal model to an existing continuum model and predict the extent to which dynamic spectrin network connectivity can protect against failure in the case of a red cell subjected to an applied strain. The methods presented here could form the basis of disease- and patient-specific computational studies of hereditary diseases affecting the red cell cytoskeleton. Red blood cells are responsible for delivering oxygen to tissues throughout the body. These terminally differentiated cells have developed a fascinating flexibility and resiliency that is critical to navigating the circulatory system. Far from being rigid bodies, red blood cells adopt biconcave disk shapes at equilibrium, parachute-like shapes as they move between large vessels and small capillaries, and more extreme shapes as they traverse the endothelial slits of the spleen. Understanding the remarkable mechanical properties that allow red cells to experience such large deformations while maintaining structural integrity is a fundamental question in physiology that may help advance treatments of genetic disorders such as hereditary spherocytosis and elliptocytosis that affect red cell flexibility and can lead to severe anemia. In this work, we present a model of the red blood cell cytoskeleton based on cryoelectron tomography data. We develop an image processing technique to gather statistics from these data and use these statistics to generate a random entropic network to model the cytoskeleton. We then simulate the behavior of the resulting red blood cell in flow. As we demonstrate through simulations, this method makes it possible to control microstructural details of the cytoskeleton, for example by including dynamic remodeling.

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