Erythroblastic islands foster granulopoiesis in parallel to terminal erythropoiesis

Abstract

The erythroblastic island (EBI), composed of a central macrophage surrounded by maturing erythroblasts, is the erythroid precursor niche. Despite numerous studies, its precise composition is still unclear. Using multispectral imaging flow cytometry (IFC), in vitro island reconstitution, and single cell RNA-sequencing (scRNA-seq) of adult mouse bone marrow EBI-component cells enriched by gradient sedimentation, we present evidence that the CD11b+-cells present in the EBIs are neutrophil precursors specifically associated with bone marrow EBI macrophages, indicating that erythro-(myelo)-blastic islands are a site for both terminal granulopoiesis and erythropoiesis. We further demonstrate that the balance between these dominant and terminal differentiation programs is dynamically regulated within this bone marrow niche by pathophysiological states, favoring granulopoiesis during anemia of inflammation, or erythropoiesis after erythropoietin (Epo) stimulation. Finally, by molecular profiling, we reveal the heterogeneity of EBI macrophages by Cellular Indexing of Transcriptome and Epitopes (CITE)-sequencing of mouse bone marrow EBIs at baseline and after Epo-stimulation in vivo and provide a searchable, online viewer of this data characterizing the macrophage subsets serving as hematopoietic niches. Taken together, our findings demonstrate that EBIs serve a dual role as niches for terminal erythropoiesis and granulopoiesis and the central macrophages adapt to optimize production of red blood cells or neutrophils.

Navigating the marrow sea towards erythromyeloblastic islands under normal and inflammatory conditions

“…Emerging technologies will also aid in our understanding of the erythromyeloblastic niche and associated anaemic conditions. Although scRNAseq may not be enough to appreciate the unique signature of the central macrophage, single-cell multiomics (CITE-seq) validated by biologic data have improved our understanding of these structures [20 ▪▪ ]. If the tight interaction of macrophages with other cell types in the islands limit the number or bias the populations of the central macrophages isolated for further studies, perhaps we must isolate deeper structures within the cell, such as the nucleus or mitochondria, for the unique cellular signature that is so important for understanding the EMBI [41].…”

“…[12] suggested that myeloid cells were also found in close association with the central macrophage in the islands isolated from the rabbit bone marrow. We knew very recently that EBIs not only support erythroid precursors, but neutrophil precursors as well, expanding our understanding of the niche and proposing renaming it to an erythromyeloblastic island (EMBI) [20 ▪▪ ].…”

“…Investigation of the EMBI population indicates that inflammation may skew the heterogeneity of these islands towards myeloid production. For instance, in both AoI mouse models, as well as direct granulopoiesis stimulation by granulocyte colony-stimulating factor (G-CSF) treatment, EMBIs have demonstrated an increased production of CD11b + cells in intimate contact with the central macrophage, compared with CD71 + cells [20 ▪▪ ].…”

Two’s company but three’s a blast!

“…In this issue of Blood, Romano et al discover that in murine bone marrow, both granulocyte and erythroid precursors develop around a single central macrophage, within a specialized niche termed erythromyeloblastic islands (EMBI). 1 Although it is well established that mammalian erythropoiesis occurs in erythroblastic islands (EBI), comprising 5 to 30 maturing red blood cell precursors surrounding a macrophage, 2 like an orchestra around a conductor, Romano et al identify that the "orchestra" constitutes granulocyte as well as erythroid precursors. Furthermore, they introduce a new concept in hematopoietic cell homeostasis: an inverse relationship between erythroid and granulocyte lineage cell numbers in EMBI that vary in response to microenvironmental cues.…”

“…In this issue of Blood, Albert et al 1 present compelling evidence that allogeneic hematopoietic stem cell transplantation (HSCT) is a highly feasible and potentially curative approach for adults with inborn errors of immunity (IEI).…”