A CD4-lineage erythro-myeloid progenitor within the adult bone marrow defines an alternative pathway for macrophage...

Tissue-resident macrophages originate from distinct developmental sources, but their adult replenishment is thought to depend exclusively on circulating monocytes. Here we identify a previously unrecognized CD4-lineage erythro-myeloid progenitor (EMPROR) in the adult bone marrow that provides an alternative pathway for macrophage generation. EMPROR cells are phenotypically and transcriptionally distinct from hematopoietic stem cells, common myeloid progenitors and monocyte precursors, lacking Csf1r and Ccr2 while expressing Cd4 and Kit. Single-cell RNA sequencing, RNA velocity analysis and lineage assays reveal macrophage, neutrophil, megakaryocytic and erythroid potential. EMPROR cells generate perivascular and tumor-associated macrophages independently of CCR2-mediated monocyte recruitment and contribute to erythroid and granulocytic lineages under inflammatory and neoplastic conditions. Transcriptomic comparisons position EMPROR cells closest to embryonic erythro-myeloid progenitors, indicating the persistence of an embryonic-like program in adult bone marrow. These findings reveal an alternative pathway of adult myelopoiesis that sustains macrophage diversity beyond the classical monocyte lineage.