The circulatory dynamics of human red blood cell homeostasis: Oxy-deoxy and PIEZO1-triggered changes

The vital function of red blood cells (RBCs) is to mediate the transport of oxygen from lungs to tissues and of CO₂ from tissues to lungs. The gas exchanges occur during capillary transits within fractions of a second. Each oxygenation-deoxygenation and deoxygenation-reoxygenation transition on hemoglobin triggers sharp changes in RBC pH, leading to downstream changes in ion fluxes, membrane potential, and cell volume. The dynamics of these changes during the variable periods between capillary transits in vivo remains a mystery inaccessible to study by current methodologies, a knowledge gap on a fundamental physiological process that is the focus of the present study. The use of a computational model of human RBC homeostasis of tested accreditation enabled a detailed investigation of the expected RBC changes during intercapillary transits, with results advancing novel insights and predictions. The predicted rates of relative RBC volume change on oxygenation-deoxygenation (oxy-deoxy) and deoxygenation-reoxygenation transitions were about 1.5%/min and -0.9%/min, respectively, far too slow to allow the cells to reach steady states in the intervals between capillary transits. The amplitude of the oxy-deoxy-reoxygenation volume fluctuations varied in proportion with the duration of the intercapillary transit intervals. Upon capillary entry, oxy-deoxy-induced changes occur concurrently with deformation-induced PIEZO1 channel activation, both processes affecting cell pH, membrane potential, and cell volume during intertransit periods. The model showed that the effects were strictly additive as expected from processes operating independently on the cell's homeostatic fabric. Analysis of the mechanisms behind these predictions revealed, for the first time, the complex interactions between oxy-deoxy and ion transport processes that ensure the long-term homeostatic stability of RBCs for optimal gas transport in physiological conditions and how these may become altered in diseased states. Possible designs of microfluidic devices to test the model predictions are discussed.