NEWS AND VIEWS NATURE MEDICINE VOLUME 19 | NUMBER 4 | APRIL 2013 399 Mammalian red blood cells (RBCs) are short- lived flexible biconcave discs, optimally adapted for transporting oxygen. They are con- tinuously replenished through a process known as erythropoiesis, where in a span of three to five cell divisions, CFUe (colony-forming unit erythroid) progenitors differentiate into erythroblasts that, in turn, mature and enucle- ate to form reticulocytes (new RBCs). A nega- tive feedback loop allows stress conditions that threaten tissue oxygen tension, such as anemia or bleeding, to accelerate RBC production (Fig. 1). It consists of an oxygen-sensing transcriptional mechanism in the kidney that compares the actual and optimal tissue oxygen levels and generates an ‘error’ signal in the form of the hormone erythropoiein (Epo), whose mag- nitude reflects the degree of stress. Epo is an essential viability factor for erythroid progeni- tors: CFUe and early erythroblasts are continu- ously generated in large excess, but the fraction of these cells that survives to complete differen- tiation is determined by Epo levels 1,2 . In culture, adult mammalian CFUe progeni- tors require no other cell type to fully differ- entiate into RBCs. However, in hematopoietic tissue, these cells differentiate in the context of a specialized niche, the erythroblastic island, where erythroblasts are attached in concentric rings to one or more central macrophages 3,4 . Progenitor niches have been described for many tissues, providing a locale that concen- trates tissue-specific nutritional and autocrine factors and integrates extracellular inputs. Studies in vitro suggested similar functions for the erythroblastic island. However, their con- tribution to erythropoiesis in vivo remained unclear. In this issue of Nature Medicine, two studies by Chow et al. 5 and Ramos et al. 6 suggest a key role for the erythroblastic island macrophage in the erythropoietic response to stress conditions such as hemolytic anemia or bleeding. Their findings point to macrophages as potential targets in the treat- ment of disorders where erythropoiesis is accelerated inappropriately. Merav Socolovsky is in the Departments of Cancer Biology and Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts, USA. e-mail: merav.socolovsky@umassmed.edu Exploring the erythroblastic island Merav Socolovsky Two new studies suggest a crucial role for macrophages in boosting the number of red blood cells produced in vivo during stress, with translational implications for disease states such as b-thalassemia and polycythemia vera (pages 429–436 and 437–445). Katie Vicari Figure 1 Erythropoiesis within and without the erythroblastic island. Erythroblasts differentiate into RBCs within the erythroblastic island (EI) niche, where they are attached to a macrophage. Differentiation is driven by a negative feedback loop, where tissue oxygen (pO 2 ) regulates the hormone Epo, an essential erythroblast viability factor (top). Macrophages amplify the response to Epo by promoting additional erythroblast cell divisions, assist in enucleation and iron uptake, and hold erythroblasts in close proximity, allowing autoregulatory interactions. It is not known whether erythroblasts repeatedly attach and detach from the erythroblastic island (dashed arrows) or whether they can differentiate entirely outside the erythroblastic island in vivo. Chow et al. 5 and Ramos et al. 6 show that macrophages contribute to the accelerated production of RBCs when pO 2 is threatened. In b-thalassemia (bottom), precipitation of excess hemoglobin a-chains (dark inclusions) destroys erythroblasts and RBCs. Paradoxically, macrophage depletion improves this condition, possibly by forcing erythroblastic island–independent erythroblast maturation, with reduced iron uptake and consequently reduced globin chain synthesis, resulting in fewer a-globin precipitates and better RBC quality. Physiological erythropoiesis EI-independent? + ? ? Blood vessel RBCs EI EI macrophage + + Epo pO 2 Autoregulation Enucleation Fe? Proliferation β-thalassemia Erythroblast Blood vessel RBCs Fe Proliferation α-globin precipitate EI-independent? EI npg © 2013 Nature America, Inc. All rights reserved.