Mesoscopic Adaptive Resolution Scheme toward understanding of interactions between sickle cell fibers

BPJ_113_1.c1.inddSickle cell disease (SCD) is a molecular disease that affects hemoglobin. To understand the altered morphologies and mechanical properties of sickle red blood cells in SCD, it is important to investigate polymerization of the mutated form of hemoglobin (HbS) and subsequent interaction with the red blood cell (RBC) membrane.

The cover image for the July 11 issue of the Biophysical Journal is an artistic rendering of several RBCs and a white blood cell in the blood flow. Some RBCs are sickle-like shape. The largest RBC in the bottom left corner is shown in the protein level. The red, blue, and green particles represent the lipid particles, spectrin proteins, and actin junctions in the RBC membrane, respectively. Inside the RBC,  a single HbS fiber consists of 14 chains of HbS tetramers arranged in a 7 double-stranded configuration. The 14 chains of HbS tetramers are twisted about a common axis in a rope-like fashion. In the image, one small yellow particle is one HbS molecule, and  56 small particles are coarse-grained as one large yellow particle.

As shown in the image, the proposed hybrid HbS fiber model seamlessly couples these two HbS fiber models at different length scales by applying a mesoscopic adaptive resolution scheme (MARS). The stiff HbS fibers interact with the RBC membrane and distort the RBC to the sickle shape. Sickle RBC morphologies are determined by the number of HbS fiber domains and the structure of each domain inside the cells. In return, the RBC membrane also suppresses the growth of the HbS fiber. In addition to irregular shapes, sickle RBCs are characterized by increased cell rigidity due to intracellular fiber structures, resulting in blood flow impairment and vaso-occlusive crises in the microcirculation.

This cover was inspired by the pressing need to understand the integrated process of HbS nucleation and polymerization, and subsequent alterations of cell morphology, which is a multi-scale process ranging from nanometers to micrometers. In order to accurately describe this process, the hybrid HbS fiber model is employed to capture the dynamic process of polymerization of HbS fibers, while maintaining the mechanical properties of polymerized HbS fibers, thus providing a means of bridging the subcellular and cellular phenomena in sickle cell disease.

—- Lu Lu, He Li, Xin Bian, Xuejin Li, and George Em Karniadakis

Red Blood Cell Adhesion in Sickle Cell Disease

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Millions worldwide live with sickle cell disease, the most common inherited blood disorder. Sickle cell disease is due to a single-point mutation in the ÿ-globin gene resulting in the production of abnormal hemoglobin. In the deoxygenated state, hemoglobin polymerizes to form relatively stiff filaments forcing red blood cells to assume an irregular shape. It is these “sickled” red blood cells that are thought to significantly contribute to, if not initiate, occlusion of small blood vessels resulting in microvascular infarction, severe pain, widespread organ dysfunction, and early mortality.  The hallmark of the disease is the development of spontaneous, intermittent, disabling episodes of severe pain called vaso-occlusive episodes.

Our article discusses adhesion of normal and sickle cell disease human erythrocytes to endothelial laminin.  Erythrocyte adhesion to endothelium is thought to be a critical mediator of the complicated process of vaso-occlusion in sickle cell disease. This translational work is a collaboration between investigators at the schools of Engineering and Medicine at the University of Connecticut.  When our article was accepted for publication, we thought that an image on the journal cover would be a good way to attract attention to this devastating disease and to show, at least partially, the complexity of one of its major consequences in the circulatory system. The image was created by Kostyantyn Partola, who is a first-year Ph.D. candidate in our lab. It is a three-dimensional depiction of normally and abnormally shaped sickled red blood cells interacting with endothelial cells as well as white blood cells and platelets in a human blood vessel cross-section. Some of the sickled cells are adherent to the endothelium and partially obstruct blood flow, while other cells are shown flowing freely within the blood vessel. We tried to create an interesting picture by illustrating how the interaction of cells can mediate vasoocclusion.

Please visit the website of the Cellular Mechanics Laboratory at the University of Connecticut and the Comprehensive Sickle Cell Clinical and Research Center at the University of Connecticut Health Center for more information on our research.

–Jamie Maciaszek, Biree Andemariam, Krithika Abiraman, and George Lykotrafitis