Erythropoiesis is the process by which nucleated erythroid progenitors proliferate and differentiate to generate, every second, millions of nonnucleated red cells with their unique discoid shape and membrane material properties. Here we examined the time course of appearance of individual membrane protein components during murine erythropoiesis to throw new light on our understanding of the evolution of the unique features of the red cell membrane. We found that the accumulation of all of the major transmembrane and all skeletal proteins of the mature red blood cell, except actin, accrued progressively during terminal erythroid differentiation. At the same time, and in marked contrast, accumulation of various adhesion molecules decreased. In particular, the adhesion molecule, CD44 exhibited a progressive and dramatic decrease from proerythroblast to reticulocyte; this enabled us to devise a new strategy for distinguishing unambiguously between erythroblasts at successive developmental stages. These findings provide unique insights into the genesis of red cell membrane function during erythroblast differentiation and also offer a means of defining stage-specific defects in erythroid maturation in inherited and acquired red cell disorders and in bone marrow failure syndromes.E rythropoiesis is the process by which erythroid progenitors proliferate and differentiate into nonnucleated reticulocytes. Two distinct erythroid progenitors have been functionally defined in colony assays, namely, the early-stage burst-forming uniterythroid (BFU-E) and the later stage colony-forming uniterythroid (CFU-E) progenitor (1). The earliest morphologically recognizable erythroblast in hematopoietic tissues is the proerythroblast, which undergoes 3-4 mitoses to produce reticulocytes. Morphologically distinct populations of erythroblasts are produced by each successive mitosis, beginning with proerythroblasts and followed by basophilic, polychromatic, and orthochromatic erythroblasts. Finally, orthochromatic erythroblasts expel their nuclei to generate reticulocytes. This ordered differentiation process is accompanied by decreases in cell size, enhanced chromatin condensation, progressive hemoglobinization, and marked changes in membrane organization.During recent decades, detailed characterization of the protein composition and structural organization of the mature red cell membrane has led to insights into its function (2-6). A 2-dimensional spectrin-based skeletal network consisting of ␣-and ␤-spectrin, short actin filaments, protein 4.1R, ankyrin, protein 4.2, p55, adducin, dematin, tropomyosin, and tropomodulin has been shown to regulate membrane elasticity and stability. Mutations in some of these proteins result in loss of mechanical integrity and hemolytic anemia. The skeletal network is attached to the lipid bilayer through 2 major linkages (7). The first is through ankyrin, which itself forms part of a complex of band 3, glycophorin A, RhAG, CD47, and ICAM-4, while the second involves protein 4.1R, glycophorin C, and protei...

Erythroblastic islands, the specialized niches in which erythroid precursors proliferate, differentiate, and enucleate, were first described 50 years ago by analysis of transmission electron micrographs of bone marrow. These hematopoietic subcompartments are composed of erythroblasts surrounding a central macrophage. A hiatus of several decades followed, during which the importance of erythroblastic islands remained unrecognized as erythroid progenitors were shown to possess an autonomous differentiation program with a capacity to complete terminal differentiation in vitro in the presence of erythropoietin but without macrophages. However, as the extent of proliferation, differentiation, and enucleation efficiency documented in vivo could not be recapitulated in vitro, a resurgence of interest in erythroid niches has emerged. We now have an increased molecular understanding of processes operating within erythroid niches, including cell-cell and cellextracellular matrix adhesion, positive and negative regulatory feedback, and central macrophage function. These features of erythroblast islands represent important contributors to normal erythroid development, as well as altered erythropoiesis found in such diverse diseases as anemia of inflammation and chronic disease, myelodysplasia, thalassemia, and malarial anemia. Coupling of historical, current, and future insights will be essential to understand the tightly regulated production of red cells both in steady state and stress erythropoiesis. DiscoveryThere is a great deal of recent excitement concerning stem cell niches that regulate self-renewal and cell differentiation in the bone marrow, but it should be noted that the first description of a hematopoietic niche actually took place 50 years ago when the French hematologist, Marcel Bessis, discovered erythroblastic islands. 1 Cell-cell and cell-extracellular matrix interactions that are the hallmark of niches are increasingly being recognized as sites of both positive and negative regulators of cell proliferation and differentiation in many tissue types. As such, features of erythroid niches represent important contributors to normal erythroid development, as well as altered erythropoiesis found in such diverse diseases as thalassemia with its ineffective erythropoiesis, myelodysplasia (MDS) accompanied by disordered erythroid maturation, and anemia of inflammation and chronic disease secondary to perturbed iron metabolism.Bessis originally characterized the erythroblastic island as developing erythroblasts surrounding a central macrophage, based on careful analysis of transmission electron micrographs of sections of bone marrow (Figure 1). Erythroid islands are also present in fetal liver and spleen. 1 It is important to note that these islands are not seen in bone marrow aspirates because they are readily disrupted during smear preparation. Based on structural observations, Bessis and colleagues made a number of interesting inferences concerning the role of central macrophages. It was suggested that the macro...

Key Points Purification of staged human erythroblasts should facilitate a comprehensive cellular and molecular characterization of these cell populations. Quantification of human terminal erythropoiesis in vivo provides a powerful means for studying impaired erythropoiesis in human diseases.

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