New insights into the mechanisms of red blood cell enucleation: From basics to clinical applications

Abstract

Background: Red blood cell (RBC) enucleation is a crucial step in the process of erythropoiesis. By removing the nucleus, RBCs gain greater flexibility, enabling them to traverse narrow capillaries with ease, thereby enhancing the efficiency of oxygen and carbon dioxide transport. This transformation underscores the intricate balance between cellular structure and function essential for maintaining homeostasis.

Topic: This review delves into the multifaceted enucleation process, outlining its complex steps that encompass protein sorting, vesicle trafficking, cytoskeletal remodeling, and apoptosis regulation, while also exploring the potential of enhancing the enucleation rate of RBCs in vitro. We emphasize the intricate regulation of this process, which is orchestrated by multiple factors. This includes transcription factors that meticulously guide protein synthesis and sorting through the modulation of gene expression, as well as non-coding RNAs that play a pivotal role in post-transcriptional regulation during various stages of RBC enucleation. Additionally, macrophages participate in the enucleation process by engulfing and clearing the extruded nuclei, further ensuring the proper development of RBCs. Although many studies have deeply explored the molecular mechanisms of enucleation, the roles of apoptosis and anti-apoptotic processes in RBC enucleation remain incompletely understood.

Implication: In this review, we aim to comprehensively summarize the RBC enucleation process and explore the progress made in ex vivo RBC generation. In the future, a deeper understanding of the enucleation process could provide significant benefits to patients suffering from anemia and other related conditions.

Keywords: RBCs; apoptosis; biological fundamentals; enucleation; erythropoiesis; methodology.

FIGURE 1

This diagram elaborates on the intricate developmental trajectory of proerythroblast differentiating into a mature erythrocyte. It meticulously depicts the significant morphological changes where the Proerythroblast gradually transforms into a Polychromatic erythroblast, initiating hemoglobin synthesis at this juncture, a pivotal step for the subsequent oxygen transport function of erythrocytes. As the developmental progression deepens, erythrocytes undergo a hallmark event‐enucleation, the expulsion of the cell nucleus. This process necessitates the highly condensed state of chromatin and involves intricate molecular mechanisms, including precise protein sorting, the participation of crucial transcription factors such as gata1, hexim1, tal1, and klf1, dynamic remodeling of the F‐actin cytoskeleton, regulation by non‐coding RNAs (including miR‐30a, miR‐34a, miR‐9, etc.), and intricate modulation of cellular autophagy. These molecular mechanisms work in concert, guiding the precursor erythroid cells through the transition from nucleated to anucleated erythrocytes, ultimately shaping the mature, anucleated erythrocytes with their characteristic biconcave discoid morphology. These erythrocytes are then released into the circulatory system to perform their core physiological function—oxygen transport throughout the body. The visual representation in this diagram profoundly reveals the delicate balance and interdependence between gene expression patterns, protein synthesis activities, and cellular structural reorganization, which are vital for the successful generation and maintenance of functional erythrocytes.