Independent production of distinct monocyte subsets by granulocyte-monocyte progenitors (GMPS) and monocyte-dendritic cell progenitors (MDPS)

Abstract

Myelopoiesis, the production of myeloid cells by hematopoietic stem and progenitor cells, must be carefully regulated to support immune surveillance in the steady-state and meet the additional demands of emergency conditions such as infection. The current widely-accepted model of myelopoiesis describes the production of neutrophils by granulocyte-monocyte progenitors (GMPs), which also yield monocytes and dendritic cells (DCs) via monocyte-DC progenitors (MDPs). However, our studies have revealed that murine GMPs do not give rise to MDPs, and that conventional and plasmacytoid DCs (cDCs and pDCs) are produced by MDPs but not GMPs. Instead, we have discovered that GMPs and MDPs arise separately, and that both yield Ly6Chi monocytes and Ly6C- CD43+ monocytes. However, GMP- and MDP-derived Ly6Chi monocytes are morphologically distinct and exhibit differences in gene expression that are defined by their origins. GMPs produce a subset of Ly6Chi monocytes that are larger and more granular than MDP-derived Ly6Chi monocytes, and enriched for granule proteins including myeloperoxidase. In contrast, monocyte-derived DCs arise from the MDP pathway and are not produced by GMPs. We also show that the GMP and MDP pathways are mobilized independently in response to microbial stimuli. Lipopolysaccharide administration increases neutrophil and monocyte production by GMPs, while CpG DNA promotes monocyte and cDC production by MDPs. Thus, the existence of two independent pathways of monocyte differentiation permits the production of specific combinations of myeloid cell types during the emergency myelopoiesis response to pathogens via differential targeting of GMPs and MDPs.