Anchoring at an island to relieve stress.

S tress erythropoiesis is increasingly recognized as more than simply an expansion of steady-state erythropoiesis. Rather, it is a process arising from unique progenitor cells with distinct quantitative and qualitative cytokine requirements. Increased erythropoietin (Epo) levels resulting from kidney hypoxia due to anemia, initiate the response of stress erythropoiesis. A progenitor, named stress burst-forming unit-erythroid (BFU-E) and found in the spleen but not in bone marrow of mice subjected to erythropoietic stress, has been identified as able to produce erythroid colonies when exposed to high Epo concentrations with no additional in vitro requirement for stem cell factor (SCF) or interleukin-3, in contrast to bone marrow BFU-E.2 Stress BFU-E are stimulated to expand by bone morphogenetic protein 4 (BMP4) produced in the spleen in response to hypoxia. Erythropoietic stress leads to mobilization of bone marrow progenitors which home to the spleen and differentiate into stress BFU-E, under the influence of BMP4 and Hedgehog signaling.3 Nevertheless, homeostatic erythropoietic pathways like SCF– c-kit and glucocorticoid receptor–mediated signaling are also vital for successful stress erythropoietic response in vivo.4,5 Stress erythropoiesis has been shown to be impaired in gene-targeted mouse models where steady-state erythropoiesis is fairly normal, like in mice with deficiency of growth arrest–specific gene 6 (Gas6)6 or conditional deletion of focal adhesion kinase (FAK).7 On the other hand, stress erythropoiesis in the splenic microenvironment can be successful in cases where homeostatic erythropoiesis in the bone marrow is pathologic, like in deficiency of Rac1 and Rac2 GTPases.8 The interactions of erythroid progenitors and precursors with macrophages and extracellular matrix components such as fibronectin and laminin within erythroblastic islands are critical for optimal proliferation, survival, differentiation, and terminal maturation into red blood cells.9 4 1 and 5 1 integrins are the main erythroid cell receptors that interact with fibronectin. Whereas 4 1 mediates adhesion to several sites on fibronectin, 5 1 binds predominantly to the Arg-Gly-Asp (RGD) domain. 5 expression is noted to be higher in early erythroblasts, whereas 4 is widely expressed throughout nucleated erythroid cells. VCAM-1 represents the major and preferred ligand for 4 1 in stroma cells. The role of these integrins and their ligands in erythropoiesis has been extensively studied by in vitro and in vivo assays, frequently with contradictory results. In this issue, Ulyanova and colleagues offer a resolution to these conflicts, using a systematic in vivo genetic approach to analyze the erythropoietic phenotype after conditional deletion of 1, 4, or VCAM-1 in hematopoietic tissues of adult mice.1 1 deletion produces 1 / mice which demonstrate deficiency of 5 1 and compensatory overexpression of 4 7 in erythroid cells. 4 /