Delineating the origins, developmental programs and homeostatic functions of tissue-resident macrophages.

A literature covering 150 years of research indicates that macrophages are a diverse family of professional phagocytes that continuously explore their environment, recognize and scavenge pathogens, unfit cells, cell debris as well as metabolites, and produce a large range of bioactive molecules and growth factors. A new paradigm suggests that most tissue-resident macrophages originate from fetal precursors that colonize developing organs and self-maintain independently of bone marrow-derived cells throughout life. The differentiation of these precursors is driven by a core macrophage transcriptional program and immediately followed by their specification through expression of tissue-specific transcriptional regulators early during embryogenesis. Despite our increasing understanding of ontogeny and genetic programs that shape differentiation processes and functions of macrophages, the precise developmental trajectories of tissue-resident macrophages remain undefined. Here, I review current models of fetal hematopoietic waves, possible routes of macrophage development and their roles during homeostasis. Further, transgenic mouse models are discussed providing a toolset to study the developmentally and functionally distinct arms of the phagocyte system in vivo.