Erythromyeloid progenitors give rise to a population of osteoclasts contributing to bone homeostasis and repair

The osteoclast is a multinucleated monocyte/macrophage lineage cell that degrades bone. Here we used lineage tracing studies, labeling cells expressing Cx3cr1, Csf1r, or Flt3 to identify the precursors of osteoclast in mice. We identified an erythromyeloid progenitor (EMP)-derived osteoclast precursor population. Yolk-sac macrophages of EMP origin produced neonatal osteoclasts that can create a space for postnatal bone marrow hematopoiesis. Furthermore, EMPs gave rise to long-lasting osteoclast precursors that contributed to postnatal bone remodeling in both physiological and pathological settings. Our single cell RNA-sequencing data showed that EMP-derived osteoclast precursors arose independently from hematopoietic stem cell (HSC) lineage and the data from fate tracking of EMP- and HSC-lineage provided a possibility of cell-cell fusion between both lineages. Cx3cr1(+) yolk-sac macrophage descendants resided in the adult spleen and parabiosis experiments showed that they migrated through the circulation to the remodeled bone after the injury.