Spatial transcriptomic analyses highlight distinct erythroid niches in mice and humans.

Erythroid cells require specialized microenvironments called erythroblastic islands (EBIs), niches comprising a central macrophage surrounded by developing erythroid precursors, to complete their maturation. Understanding EBI composition and function has been limited by two-dimensional in vitro models and the unclear composition of EBIs in human hematopoietic tissues. Using spatial transcriptomic mapping in mouse and human hematopoietic tissues during development and under stress conditions, we show that EBI architecture is unexpectedly species-specific. In mice, C1q-expressing macrophages serve as a hallmark of EBI central macrophages and mediate clearance of ejected erythroid nuclei. In humans, however, EBIs are characterized by macrophage-independent erythroid clusters in fetal liver and bone marrow, whose integrity depends critically on the adhesion molecule ICAM4. These human erythroid clusters are disrupted in myeloid diseases but can be restored with therapy. These findings redefine conventional models of erythroid niche biology and establish a framework for understanding niche dynamics across species.