Extended Data Fig. 8: Schematic representation showing the differential origin of osteoclast precursors and their differentiation.

Myb-independent early erythromyeloid progenitors (EMPs) appear around E7-7.5 in the yolk-sac and differentiate into Csf1r+ yolk-sac macrophage (YS Mac) at E8.5 without passing through monocyte intermediates. YS Mac differentiates into CX3C chemokine receptor 1 (CX3CR1) positive premacrophage (pMac), resulting in a significant source of yolk-sac-derived macrophages. Late EMPs emerge in the yolk-sac at E8.5 and migrate to the fetal liver to produce Myb-expressing fetal liver (FL) myeloid progenitors (MP), resulting in FL monocyte (FL Mono). Hematopoietic stem cell precursors (pro-HSCs) emerge at E10.5. Pro-HSCs migrate to the fetal liver around E12 and turns to fetal HSCs, which later shift to the bone marrow. Bone marrow HSCs eventually can establish the circulating monocyte-derived macrophages. YS-derived macrophages differentiate into osteoclast (YS-derived Oc) in the neonatal bone with possible cell-cell fusion with HSC-derived Oc precursors. Cx3cr1+ yolk-sac macrophage descendants in the spleen can provide long-lasting Oc that contribute to the postnatal bone remodeling after injury via the bloodstream.