l-arginine import via cationic amino acid transporter CAT1 is essential for both differentiation and proliferation of erythrocytes

Abstract

In the present study, we examined the role in hematopoiesis of cationic amino acid transporter 1 (CAT1), which transports l-arginine, l-lysine, l-ornithine, and l-histidine. The expression level of human CAT1 (hCAT1) mRNA in mononuclear cells (MNCs) fractionated according to lineage-selective markers was examined by reverse transcriptase-polymerase chain reaction. The expression of CAT1 in glycophorin A-positive erythroid cells was 8 times higher than in nonfractionated MNC (control) cells. Characteristics of l-arginine uptake by K562 cells, an established leukemic cell line used as an erythroid model, were similar to those of CAT1 in regards to saturation kinetics, sodium independence, and substantial inhibition of l-arginine uptake by N-ethylmaleimide, which is a specific inhibitor of system y+ amino acid transporter. Removal of l-arginine from the culture medium prevented both proliferation and differentiation of K562 cells, while removal of l-lysine or l-histidine had little effect on differentiation, though proliferation was blocked. Hematopoietic stem cells obtained from human cord blood failed to develop into erythroid cells in the absence of l-arginine in the culture medium. These findings indicate that hCAT1 is involved in erythroid hematopoiesis through its role in importing l-arginine, which appears to be essential for the differentiation of red blood cells.