Ontogeny of myeloid cells

Abstract

Granulocytes, monocytes, macrophages, and dendritic cells (DCs) represent a subgroup of leukocytes, collectively called myeloid cells. During the embryonic development of mammalians, myelopoiesis occurs in a stepwise fashion that begins in the yolk sac and ends up in the bone marrow (BM). During this process, these early monocyte progenitors colonize various organs such as the brain, liver, skin, and lungs and differentiate into resident macrophages that will self-maintain throughout life. DCs are constantly replenished from BM precursors but can also arise from monocytes in inflammatory conditions. In this review, we summarize the different types of myeloid cells and discuss new insights into their early origin and development in mice and humans from fetal to adult life. We specifically focus on the function of monocytes, macrophages, and DCs at these different developmental stages and on the intrinsic and environmental influences that may drive these adaptations.

Keywords: TLR; cytokine; dendritic cell; fetus; macrophage; microbiota; monocyte; neonate.

Figure 1

The origin of monocytes and macrophages throughout development. Tissue resident macrophages arise at different stages of development and derive from at least three different sources. During early embryonic development, yolk sac-derived myeloid progenitors give rise to microglia in the brain, Kupffer cells in the liver, and Langerhans cells in the skin. Once fetal liver hematopoiesis has started (E10.5 in mice), fetal liver-derived monocytes differentiate into tissue macrophages and contribute to the Langerhans cell pool in the skin and lamina propria macrophages in the gut. They also seed the lung just before birth. After birth, these cells rapidly differentiate into long-lived alveolar macrophages (AMF) via a “pre-AMF,” intermediate differentiation stage. Fetal monocyte-derived Langerhans cells show vigorous proliferation after birth while lamina propria macrophages are continuously renewed via differentiation of bone marrow-derived monocytes. In addition to these resident macrophage populations, Ly6C^high monocytes can be recruited to sites of infection or injury and differentiate into inflammatory macrophages, monocyte-derived dendritic cells (Mo-DCs), or myeloid-derived suppressor cells (MDSCs).

Figure 2

Factors that can account for the different functional properties of monocytes/DCs in the course of their ontogeny. Monocytes and DCs are highly plastic, even in “steady-state” conditions. Lineage specification and function are influences by the origin of the progenitors and by environmental factors. We depict the role of the materno-fetal immunomodulatory environment (red arrows) and the direct or indirect priming effects of microbial-derived signals that are encountered after birth (green arrows).