Terminal maturation of human reticulocytes to red blood cells by extensive remodelling and progressive liquid ordering of membrane lipids

Abstract

In the age of "omics", lipidomics of erythropoiesis is still missing. How reticulocytes mature in the circulation into functional erythrocytes is also for the most part unknown, beyond the lipidomics level. We have characterized here the lipid content of two subpopulations of peripheral reticulocytes of different maturity and three of erythrocytes of different age. Reticulocytes undergo profound changes in membrane lipid composition as they mature in the vasculature. Sphingomyelin and cholesterol increase, whereas phosphatidylcholine and phosphatidylserine decrease, relative to total lipids, from young reticulocytes to mature erythrocytes, suggesting that the area of the membrane in liquid-ordered state increases. The relative amounts of the more than 70 phospholipid subclasses evaluated here also change in the process. As peripheral reticulocytes and erythrocytes are unable of de-novo phospholipid synthesis, such remodeling likely requires selective removal of phospholipids from the membrane or their exchange with plasma or both. It has to be investigated whether this process might involve lipid transfer proteins that, when defective, such as in neuroacantocytosis syndromes, result in altered erythrocyte morphology. These findings not only shed light on fundamental aspects of red blood cell physiology and erythropoiesis but also raise intriguing questions surrounding protein-lipid interactions, membrane architecture, and lipid trafficking mechanisms.