Our paper describes a bone marrow progenitor that gives rise to monocytes, macrophages, and dendritic cells (DC), but not to any other cell lineage. This is an interesting finding because it establishes a lineage relationship between macrophages and DC—two cell types that play essential roles in development, maintenance of tissue homeostasis, tolerance, and regulation of inflammation and the immune response.

“Our paper describes a bone marrow progenitor that gives rise to monocytes, macrophages, and dendritic cells (DC), but not to any other cell lineage.”

In contrast to B and T lymphocytes, the origins and differentiation pathways of macrophages and DC are not well understood. This is due in large part to their phenotypic heterogeneity and dispersed tissue distribution, and also to their limited proliferative capacity, which has hampered their study in vivo.

The discovery of this progenitor presents a potential tool for studying the molecular mechanisms involved in differentiation of macrophages and DC in other tissues—from microglial cells in the brain to bone osteoclasts, kupffer cells in the liver, langerhans cells in the skin, alveolar macrophages, as well as different macrophages and DCs in the kidney and intestine. For this reason our paper has been cited from a variety of different but related fields.

Our paper describes a new discovery of a bone marrow progenitor common for, and restricted to, cells of the mononuclear phagocyte system (MPS). Although the existence of such a bone marrow progenitor had been hypothesized by Ralph van Furth in the 1970s, the proof of its existence had to wait for modern technologies.

We took advantage of new technologies, including genetically labeled reporter mice, in vitro clonal analysis, and adoptive transfer techniques, followed by multi-color flow cytometry in order to perform careful analysis of the differentiation potential of this progenitor both at the clonal level in vitro, as well as in vivo.

We felt it was critical to carefully characterize this cell population, in order to ensure that we avoided potential contaminants such as stem cells, and also to minimize the possibility that we were studying a heterogeneous cell population, rather than a bipotent progenitor population.

Ilya Metchnikov first demonstrated the importance of macrophages to the immune system over 100 years ago. These cells engulf and destroy pathogens such as bacteria, but they also clean up tissues by taking up dead cells and debris, molecules, and toxins. Since their initial discovery, several different types of macrophages have been described in different tissues.

Some 30 years ago dendritic cells (DC) were discovered and shown to be specialized for processing and presenting foreign antigens to T lymphocytes—cells involved in long-term immunity to pathogenic microorganisms. Our study showed that certain types of macrophages and DC arise from a common progenitor in the bone marrow.

This finding may be used as a tool to better understand the development and function of different macrophage and dendritic cells in the body, and thus could have therapeutic implications in inflammatory disorders, autoimmune diseases, osteoporosis, histiocytoses, or cancer.

We have been interested in the cells of the MPS for several years. We recently used the same reporter mouse system to describe the major monocyte subsets in mice and their counterparts in humans.

In these mice, the gene encoding the receptor for the chemokine receptor CX3CR1 is replaced with a gene encoding green fluorescent protein. Because blood monocytes as well as several macrophage and DC subsets express CX3CR1, we hypothesized that this receptor might also be expressed by their immediate progenitors in the bone marrow.