Understanding terminal erythropoiesis: An update on chromatin condensation, enucleation, and reticulocyte maturation

A characteristic feature of terminal erythropoiesis in mammals is extrusion of the highly condensed nucleus out of the cytoplasm. Other vertebrates, including fish, reptiles, amphibians, and birds, undergo nuclear condensation but do not enucleate. Enucleation provides mammals evolutionary advantages by gaining extra space for hemoglobin and being more flexible to migrate through capillaries. Nascent reticulocytes further mature into red blood cells through membrane and proteome remodeling and organelle clearance. Over the past decade, novel molecular mechanisms and signaling pathways have been uncovered that play important roles in chromatin condensation, enucleation, and reticulocyte maturation. These advances not only increase understanding of the physiology of erythropoiesis, but also facilitate efforts in generating in vitro red blood cells for various translational application. In the present review, recent studies in epigenetic modification and release of histones during chromatin condensation are highlighted. New insights in enucleation, including protein sorting, vesicle trafficking, transcriptional regulation, noncoding RNA, cytoskeleton remodeling, erythroblastic islands, and cytokinesis, are summarized. Moreover, organelle clearance and proteolysis mediated by ubiquitin-proteasome degradation during reticulocytes maturation is also examined. Perspectives for future directions in this rapidly evolving research area are also provided.