Abstract
The spleen, the largest secondary lymphoid organ in humans, not only fulfils a broad range of immune functions, but also plays an important role in red blood cell’s (RBC) life cycle. Although much progress has been made to elucidate the critical biological processes involved in the maturation of young RBCs (reticulocytes) as well as removal of senescent RBCs in the spleen, the underlying mechanisms driving these processes are still obscure. Herein, we perform a computational study to simulate the passage of RBCs through interendothelial slits (IES) in the spleen at different stages of their lifespan and investigate the role of the spleen in facilitating the maturation of reticulocytes and in clearing the senescent RBCs. Our simulations reveal that at the beginning of the RBC life cycle, intracellular non-deformable particles in reticulocytes can be biomechanically expelled from the cell upon passage through IES, an insightful explanation of why this peculiar “pitting” process is spleen-specific. Our results also show that immature RBCs shed surface area by releasing vesicles after crossing IES and progressively acquire the biconcave shape of mature RBCs. These findings likely explain why RBCs from splenectomized patients are significantly larger than those from nonsplenectomized subjects. Finally, we show that at the end of their life span, senescent RBCs are not only retained by IES due to reduced deformability but also become susceptible to mechanical lysis under shear stress. This finding supports the recent hypothesis that transformation into a hemolyzed ghost is a prerequisite for phagocytosis of senescent RBCs. Altogether, our computational investigation illustrates critical biological processes in the spleen that cannot be observed in vivo or in vitro and offer insights into the role of the spleen in the RBC physiology.
Highlights
The spleen, the largest secondary lymphoid organ in the human immune system, works as a drainage network that prevents pathogenic microorganisms from remaining and multiplying in the bloodstream through innate phagocytosis or adaptive responses operated by lymphocytes and antibodies [1, 2]
We perform a computational study to simulate the passage of red blood cell (RBC) through interendothelial slits (IES) in the spleen at different stages of their lifespan, a critical biological process that cannot be observed in humans
Our simulation results illustrate a specific role of spleen in shaping young RBCs, which points to a probable missing step in current in vitro RBC culture protocols that fail to generate a majority of typical biconcave RBCs
Summary
The spleen, the largest secondary lymphoid organ in the human immune system, works as a drainage network that prevents pathogenic microorganisms from remaining and multiplying in the bloodstream through innate phagocytosis or adaptive responses operated by lymphocytes and antibodies [1, 2]. About 10–20% of blood entering the spleen is directed into the so-called open circulation, where RBCs navigate slowly and come in very close contact to abundant red pulp macrophages that can recognize surface alterations of RBCs through ‘ligand-receptor’ interactions and engulf the senescent and pathologically altered RBCs through phagocytosis [7,8,9]. RBCs with compromised deformability, such as the aged RBCs, are retained mechanically by IES.
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