BCL11A-dependent redox regulation in a splenic B cell subpopulation supports erythroid recovery from anemic stress

Abstract The spleen serves as a key site for enhanced erythroid output during anemic stress. While erythroblastic island macrophages are well-established mediators of stress erythropoiesis, the roles of other immune cells remain less defined. Here we show that a specific subset of splenic B cells promotes erythroid recovery under anemic stress. Single-cell transcriptomic profiling of murine spleens from acute and chronic anemia models revealed a distinct B cell subset with elevated expression of hemoglobin and redox-associated transcripts. Mechanistically, the transcription factor BCL11A regulates antioxidant gene programs in these B cells, enhancing their redox capacity and promoting erythroid regeneration during anemic stress. Extending these findings to humans, single-cell analysis of bone marrow from Fanconi anemia patients revealed hemoglobin-expressing, redox-active B cell subsets analogous to those in mice, suggesting a conserved redox-regulatory mechanism. Collectively, our findings expand the paradigm of stress erythropoiesis by identifying B cells as conserved extrinsic regulators of erythroid recovery and highlighting their therapeutic potential in anemia-related disorders.