In the first phase, an initial group of erythroid-committed progenitors termed burst forming unit erythroid (BFU-E) cells are produced from multipotential HSPCs and subsequently differentiate into colony forming unit erythroid (CFU-E) cells. The earlier phase originates with multipotential hematopoietic stem and progenitor cells (HSPCs) that give rise to erythroid-committed progenitors, and the latter phase is characterized by maturation of erythroid precursors into enucleated reticulocytes that undergo terminal maturation into RBCs in the circulation. Erythropoiesis lasts ∼14 days in humans and includes 7 to 8 steps over 2 major phases ( Figure 1). 2 The erythroblastic islands enhance erythropoiesis by allowing cell-cell contacts to promote survival and proliferation, and the central macrophages engulf the extruded nuclei from erythroblasts. 1 This multistep process occurs in the bone marrow of adults in dedicated areas that cluster differentiating erythroid precursors around a central macrophage, a subcompartment in the bone marrow that has been termed the erythroblastic island. As we learn more about this intricate and important process, additional opportunities to modulate erythropoiesis for therapeutic purposes will undoubtedly emerge.Įach day, the process of red blood cell (RBC) production or erythropoiesis is crucial to maintain steady-state hemoglobin levels that allow for effective oxygen transport. Finally, we provide an outlook of how our ability to measure multiple facets of this process at single-cell resolution, while accounting for the impact of human variation, will continue to refine our knowledge of erythropoiesis and how this process is perturbed in disease. We additionally discuss the insights gained by studying human genetic variation affecting erythropoiesis and highlight the discovery of BCL11A as a regulator of hemoglobin switching through genetic studies. Recent studies have also elucidated the importance of posttranscriptional regulation and highlighted additional gatekeeping mechanisms necessary for effective erythropoiesis. Here, we provide an overview of different layers of this control, ranging from cytokine signaling mechanisms that enable extrinsic regulation of RBC production to intrinsic transcriptional pathways necessary for effective erythropoiesis. Erythropoiesis is regulated at multiple levels to ensure that defective RBC maturation or overproduction can be avoided. To enable effective oxygen transport, ∼200 billion red blood cells (RBCs) need to be produced every day in the bone marrow through the fine-tuned process of erythropoiesis.
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