Decoding the erythroid niche: From single-cell programs to spatially resolved architecture in mouse and human hematopoiesis.

Abstract

Erythropoiesis is a complex, spatially constrained morphogenetic process that transforms hematopoietic progenitors into specialized, enucleated red blood cells. While decades of research have defined the cell-intrinsic transcriptional and epigenetic circuits, governed by master regulators such as GATA1 and KLF1, the critical role of the microenvironmental niche remains less understood. Recent advances in single-cell omics have revealed a multi-layered landscape in which transcriptional potential is often uncoupled from proteomic and metabolic output. The transition from dissociative single-cell sequencing to spatially resolved omics further shaped our understanding of how these molecular programs are executed in situ. This chapter summarizes the broader landscape of omics profiling while focusing on how spatial transcriptomics and proteomics are uncovering the anatomical locations of erythropoiesis within the hematopoietic organs. We highlight a significant evolutionary divergence in niche architecture: while murine terminal erythropoiesis is organized with C1q + macrophage-centered erythroblastic islands, human erythropoiesis exhibits a unique, self-sustaining capacity characterized by autonomous erythroblast clustering independent of macrophages. We further discuss the technical hurdles of spatial profiling in mineralized bone and the potential for multimodal spatial omics to link chromatin accessibility, RNA, and protein abundance within intact tissues. By integrating molecular trajectories with microanatomical context, these technologies provide a new framework for understanding ineffective erythropoiesis and identifying therapeutic targets in hematologic diseases.