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Blood, 15 July 2007, Vol. 110, No. 2, pp. 762-769.
Prepublished online as a Blood First Edition Paper on March 29, 2007; DOI 10.1182/blood-2006-12-063602.
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RED CELLS
Enhanced erythro-phagocytosis in polycythemic mice overexpressing erythropoietin
Anna Bogdanova1,
Deyan Mihov1,
Hans Lutz2,
Bianca Saam1,
Max Gassmann1, and
Johannes Vogel1
1 Institute of Veterinary Physiology, Vetsuisse Faculty and Zürich Center for Integrative Human Physiology (ZIHP), University of Zürich, Switzerland;
2 Institute of Biochemistry, Zürich, Switzerland
Adaptive mechanisms to hematocrit levels of 0.9 in our erythropoietin-overexpressing mice (tg6) include increased plasma nitric oxide levels and erythrocyte flexibility. Doubled reticulocyte counts in tg6 suggest an increased erythrocyte turnover. Here we show that compared with wild-type (wt) animals, erythrocyte lifespan in tg6 is 70% lower in tg6 mice. Transgenic mice have a younger erythrocyte population as indicated by higher intercellular water and potassium content, higher flexibility, decreased density, increased surface to volume ratio, and decreased osmotic fragility. Interestingly, despite being younger, the tg6 erythrocyte population also harbors characteristics of accelerated aging such as an increased band 4.1a to 4.1b ratio, signs of oxidative stress, or decreased surface CD47 and sialic acids. In tg6, in vivo tracking of PKH26-labeled erythrocytes revealed dramatically increased erythrocyte incorporation by their liver macrophages. In vitro experiments showed that tg6 macrophages are more active than wt macrophages and that tg6 erythrocytes are more attractive for macrophages than wt ones. In conclusion, in tg6 mice erythrocyte aging is accelerated, which results, together with an increased number and activity of their macrophages, in enhanced erythrocyte clearance. Our data points toward a new mechanism down-regulating red cell mass in excessive erythrocytosis in mice.
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