Erythroblastic islands: niches for erythropoiesis

Abstract

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 cell-extracellular 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.

Joel Anne Chasis and Narla Mohandas

Figure 1

Micrographs of erythroblastic islands. (A) Transmission electron micrograph of an erythroblastic island isolated from rat bone marrow. Note the extensive cell-cell contact. (B) Scanning electron micrograph of an isolated erythroblastic island. The inset shows an optical microscopic image of the same structure. Note the presence of an enucleating erythroblast () and a multilobulated reticulocyte (). (C) Confocal immunofluorescence image of an island reconstituted from freshly harvested mouse bone marrow cells stained with erythroid-specific marker (red), macrophage marker (green) and DNA probe (blue). Central macrophage is indicated by an arrow and a multilobulated reticulocyte by an arrowhead. (Panels A and B are courtesy of Michel Prenant of France, and panel C is reprinted from Lee et al with permission from the American Society of Hematology.) Illustration by Paulette Dennis.

Figure 2

Proliferation and differentiation processes occurring within the erythroid niche. Early-stage erythroblasts are larger cells with centrally located nuclei; more differentiated erythroblasts are smaller cells containing nuclei located adjacent to plasma membranes. Expelled nuclei undergo phagocytosis by central macrophage. Young multilobulated reticulocytes are initially attached to the macrophage surface and later detach. Illustration by Paulette Dennis.

Figure 3

Erythroblast-macrophage adhesive interactions in the erythroid niche. Interactions illustrated include erythroblast α₄β₁ binding macrophage VCAM-1; erythroblast ICAM-4 binding macrophage α_⋁ integrin; homophilic binding mediated by Emp between erythroblast and macrophage. Illustration by Paulette Dennis.

Figure 4

Schematic representation of negative regulatory factors in erythroid niche. Erythropoiesis is affected by (1) increased circulating levels of cytokines, chemokines and interleukins; (2) secretion of these factors by the central macrophage; and (3) perturbations in the extracellular matrix. Illustration by Paulette Dennis.