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Single-cell O 2 exchange imaging shows that cytoplasmic diffusion is a dominant barrier to efficient gas transport in red blood cells
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Single-cell O 2 exchange imaging shows that cytoplasmic diffusion is a dominant barrier to efficient gas transport in red blood cells
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Single-cell O 2 exchange imaging shows that cytoplasmic diffusion is a dominant barrier to efficient gas transport in red blood cells
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Journal Article
Single-cell O 2 exchange imaging shows that cytoplasmic diffusion is a dominant barrier to efficient gas transport in red blood cells
2020
Overview
Blood is routinely tested for gas-carrying capacity (total hemoglobin), but this cannot determine the speed at which red blood cells (RBCs) exchange gases. Such information is critical for evaluating the physiological fitness of RBCs, which have very limited capillary transit times (<1 s) for turning over substantial volumes of gas. We developed a method to quantify gas exchange in individual RBCs and used it to show that restricted diffusion, imposed by hemoglobin crowding, is a major barrier to gas flows. Consequently, hematological disorders manifesting a change in cell shape or hemoglobin concentration have uncharted implications on gas exchange, which we illustrate using inherited anemias. With its single-cell resolution, the method can identify physiologically inferior subpopulations, providing a clinically useful appraisal of blood quality. Disorders of oxygen transport are commonly attributed to inadequate carrying capacity (anemia) but may also relate to inefficient gas exchange by red blood cells (RBCs), a process that is poorly characterized yet assumed to be rapid. Without direct measurements of gas exchange at the single-cell level, the barriers to O 2 transport and their relationship with hematological disorders remain ill defined. We developed a method to track the flow of O 2 in individual RBCs by combining ultrarapid solution switching (to manipulate gas tension) with single-cell O 2 saturation fluorescence microscopy. O 2 unloading from RBCs was considerably slower than previously estimated in acellular hemoglobin solutions, indicating the presence of diffusional barriers in intact cells. Rate-limiting diffusion across cytoplasm was demonstrated by osmotically induced changes to hemoglobin concentration (i.e., diffusive tortuosity) and cell size (i.e., diffusion pathlength) and by comparing wild-type cells with hemoglobin H (HbH) thalassemia (shorter pathlength and reduced tortuosity) and hereditary spherocytosis (HS; expanded pathlength). Analysis of the distribution of O 2 unloading rates in HS RBCs identified a subpopulation of spherocytes with greatly impaired gas exchange. Tortuosity imposed by hemoglobin was verified by demonstrating restricted diffusivity of CO 2 , an acidic gas, from the dissipative spread of photolytically uncaged H + ions across cytoplasm. Our findings indicate that cytoplasmic diffusion, determined by pathlength and tortuosity, is a major barrier to efficient gas handling by RBCs. Consequently, changes in RBC shape and hemoglobin concentration, which are common manifestations of hematological disorders, can have hitherto unrecognized and clinically significant implications on gas exchange.
