Abstract
Human red blood cells (RBCs) have a circulatory lifespan of about four months. Under constant oxidative and mechanical stress, but devoid of organelles and deprived of biosynthetic capacity for protein renewal, RBCs undergo substantial homeostatic changes, progressive densification followed by late density reversal among others, changes assumed to have been harnessed by evolution to sustain the rheological competence of the RBCs for as long as possible. The unknown mechanisms by which this is achieved are the subject of this investigation. Each RBC traverses capillaries between 1000 and 2000 times per day, roughly one transit per minute. A dedicated Lifespan model of RBC homeostasis was developed as an extension of the RCM introduced in the previous paper to explore the cumulative patterns predicted for repetitive capillary transits over a standardized lifespan period of 120 days, using experimental data to constrain the range of acceptable model outcomes. Capillary transits were simulated by periods of elevated cell/medium volume ratios and by transient deformation-induced permeability changes attributed to PIEZO1 channel mediation as outlined in the previous paper. The first unexpected finding was that quantal density changes generated during single capillary transits cease accumulating after a few days and cannot account for the observed progressive densification of RBCs on their own, thus ruling out the quantal hypothesis. The second unexpected finding was that the documented patterns of RBC densification and late reversal could only be emulated by the implementation of a strict time-course of decay in the activities of the calcium and Na/K pumps, suggestive of a selective mechanism enabling the extended longevity of RBCs. The densification pattern over most of the circulatory lifespan was determined by calcium pump decay whereas late density reversal was shaped by the pattern of Na/K pump decay. A third finding was that both quantal changes and pump-decay regimes were necessary to account for the documented lifespan pattern, neither sufficient on their own. A fourth new finding revealed that RBCs exposed to levels of PIEZO1-medited calcium permeation above certain thresholds in the circulation could develop a pattern of early or late hyperdense collapse followed by delayed density reversal. When tested over much reduced lifespan periods the results reproduced the known circulatory fate of irreversible sickle cells, the cell subpopulation responsible for vaso-occlusion and for most of the clinical manifestations of sickle cell disease. Analysis of the results provided an insightful new understanding of the mechanisms driving the changes in RBC homeostasis during circulatory aging in health and disease.
Highlights
Bridging the information gained from the study of single capillary transits [1] to the full red blood cells (RBCs) lifespan proved a formidable challenge, impossible to approach with repetitive dynamic state pages in the RCM
The results relegated the cumulative mechanism to a secondary role and exposed surprising critical roles for the declining patterns of the calcium and sodium-potassium pumps, as if harnessed by evolution to extend the circulatory longevity of cells within volume ranges that enable optimal rheological performance
Operation of the Lifespan model generates .csv files containing the results of simulations with identical format to the one generated by the core RCM programme explained in detail in the comprehensive User Guide open to download from the GitHub repository together with the RCM .jar and Lifespan .jar programmes
Summary
Bridging the information gained from the study of single capillary transits [1] to the full RBC lifespan proved a formidable challenge, impossible to approach with repetitive dynamic state pages in the RCM. To undertake a proper lifespan study it became necessary to reset the core RCM into a new framework dedicated to follow the homeostatic changes of RBCs throughout their long circulatory journey. This new framework was developed by one of us (SR) and labelled the Lifespan model. The Lifespan model enables detailed explorations of the multiple factors shaping the changes RBCs experience in the circulation. The simulations confirmed the versatility and potential of the Lifespan model as a dedicated tool for investigating the mechanisms that control the hydration condition of RBCs during circulatory aging in health and disease
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