Macrophages and osteoclasts stem from a bipotent progenitor downstream of a macrophage/osteoclast/dendritic cell progenitor.

Abstract

Monocytes/macrophages (MΦs), osteoclasts (OCs), and dendritic cells (DCs) are closely related cell types of high clinical significance, but the exact steps in their lineage commitment are unclear. In studies on MΦ and DC development, OC development is generally not addressed. Furthermore, findings on DC development are confusing, because monocytes can also differentiate into DC-like cells. To resolve these issues, we have examined the development of monocytes/MΦs, OCs, and DCs from common progenitors, using the homeostatic driver cytokines macrophage colony-stimulating factor, RANK ligand (L), and Flt3L. In mouse bone marrow, B220^-CD11b^low/-c-Kit⁺c-Fms⁺ cells could be dissected into a CD27⁺Flt3⁺ population that proved oligopotent for MΦ/OC/DC development (MODP) and a CD27^low/-Flt3^- population that proved bipotent for MΦ/OC development (MOP). Developmental potential and relationship of MODP and downstream MOP populations are demonstrated by differentiation cultures, functional analysis of MΦ/OC/DC offspring, and genome-wide messenger RNA expression analysis. A common DC progenitor (CDP) has been described as committed to plasmacytoid and conventional DC development. However, the human CDP proved identical to the MODP population, whereas the mouse CDP largely overlapped with the MODP population and was accordingly oligopotent for MΦ, OC, and DC development. The CX₃CR1⁺ MΦ/DC progenitor (MDP) population described in the mouse generated MΦs and OCs but not DCs. Thus, monocytes/MΦs, OCs, and DCs share a common progenitor that gives rise to a bipotent MΦ/OC progenitor, but a dedicated DC progenitor is currently undefined. The definition of these progenitor populations may serve diagnostics and interventions in diseases with pathogenic activity of MΦs, OCs, or DCs.