The development and maintenance of resident macrophages

Abstract

The molecular and cellular mechanisms that underlie the many roles of macrophages in health and disease states in vivo remain poorly understood. The purpose of this Review is to present and discuss current knowledge on the developmental biology of macrophages, as it underlies the concept of a layered myeloid system composed of 'resident' macrophages that originate mainly from progenitor cells generated in the yolk sac and of 'passenger' or 'transitory' myeloid cells that originate and renew from bone marrow hematopoietic stem cells, and to provide a framework for investigating the functions of macrophages in vivo.

Figure 1

Time scale of hematopoietic progenitors development in the mouse embryo.There are three successive but overlapping waves of hematopoietic progenitors during development, all of which have the potential to give rise to fetal macrophages. They can be distinguished by the hematopoietic niches exist where the progenitors expand and differentiate during development (upper panel), the yolk sac (primitive progenitors in green and EMP in blue), the fetal liver (EMP and HSC), and finally the bone marrow (HSC, orange). While primitive progenitors are only described in a small time window (middle panel), definitive progenitors (including EMPs and HSCs) co-exist during most fetal development in the fetal liver. Only HSC-derived hematopoiesis then shifts to the bone marrow niche. The three waves of progenitor can also be distinguished by their differentiation potential in vivo (lower panel). Primitive progenitors are restricted to the erythroid or the myeloid lineages, while EMP have both erythroid and myeloid potential. EMP-derived hematopoiesis gives rise to erythrocytes, macrophages, monocytes, granulocytes and mast cells and is sufficient to support survival of embryos lacking HSCs until birth. EMP-derived macrophages persist after birth in most tissues as resident macrophages, with the exception of the intestine lamina propria. HSCs are distinguished from other progenitors by their capacity to perform long-term repopulation of all leukocytes lineages when transplanted into a conventional irradiated recipient mouse.

Figure 2

Schematic of myeloid development and maintenance in the mouse embryo and adult (see text). Circular red arrows indicate self renewal potential. Primitive progenitors do not share a common origin with endothelial cells lining the blood islands in the yolk sac (YS) and they emerge the absence of Runx1 and Myb. Within definitive hematopoiesis, HSC and EMP arise from distinct hemogenic endothelial cells through a Runx1-dependent endothelial to hematopoetic transition. Both EMP and HSC express the transcription factor Myb, and while no fetal or adult HSC-derived hematopoiesis can occur in the absence of Myb, EMPs are Myb-independent for their myeloid differentiation. EMP-derived hematopoeisis gives rises to erythrocytes and short-lived myeloid cells (monocytes, granulocytes, mast cells) that are replaced by HSC-derived cells late during gestation. EMP-derived macrophages colonise all tissues during fetal development where they specialize to their tissue of residency after birth and can persist throughout adult life by local proliferation (red arrow). Depending on the age and environmental challenges, HSC-derived cells can contribute to adult tissue resident populations.