Tissue-Resident Macrophage Ontogeny and Homeostasis Florent Ginhoux, Martin Guilliams  Immunity  Volume 44, Issue 3, Pages 439-449 (March 2016) DOI: 10.1016/j.immuni.2016.02.024 Copyright © 2016 Elsevier Inc. Terms and Conditions

Figure 1 Embryonic Hematopoiesis Three main successive waves of hematopoiesis occur during development. The first arises directly from the posterior plate mesoderm in the blood islands of the extra-embryonic yolk sac (YS) at E7.0, giving rise to progenitors as early as E7.25, which produces primitive erythroblasts and megakaryocytes and is termed primitive hematopoiesis. Progenitors giving rise to macrophages are poorly characterized. The second wave arises from the hemogenic endothelium formed between E8.0 and E8.25 in the YS and gives rise to the second wave of hematopoietic progenitors called eythro-myeloid precursors (EMPs) and is termed the transient definitive wave. Once the blood circulation is established, from E8.5 onward, EMPs migrate into the fetal liver (FL), where they expand and differentiate into multiple lineages including monocytes. Recently, using fate-mapping models, two waves of EMPs were shown to emerge in the YS. A first wave of “early” EMPs at E7.5 express the CSF-1R but not the transcription factor c-Myb and could represent primitive progenitors. A second wave of “late” EMPs emerges at E8.25, which express the transcription factor c-Myb and either give rise to YS macrophages locally or migrate to the FL through the blood circulation at E9.5 (Hoeffel et al., 2015) and could represent transient definitive progenitors. Lastly, almost concomitant with the emergence of the late EMPs at E8.5, the third wave arises in the embryo proper from hemogenic endothelium. It starts with the generation of immature HSCs in the para-aortic splanchnopleura (P-Sp) region and proceeds to give rise to fetal HSCs at E10.5 in the aorta, gonads, and mesonephros (AGM) regions (which themselves arise from the P-Sp). These precursors then colonize the FL where they establish definitive hematopoiesis and will also seed the fetal BM that will eventually lead to the generation of adult HSCs in the BM. Immunity 2016 44, 439-449DOI: (10.1016/j.immuni.2016.02.024) Copyright © 2016 Elsevier Inc. Terms and Conditions

Figure 2 Three Different Models of Fetal Macrophage Ontogeny The first model corresponds to the work of Gomez Perdiguero et al. (2015), the second to the work of Hoeffel et al. (2015), and the last to Sheng et al. (2015). Red arrow indicates the proposed major path of ontogeny and differentiation in each model. Cell colors are matched to their proposed origins. For example, whereas model 1 considers the contribution of FL monocytes unlikely, models 2 and 3 propose that these cells represent the main precursor of fetal macrophage populations, with the exception of microglia, which arise predominantly from c-Myb-independent YS macrophages. Immunity 2016 44, 439-449DOI: (10.1016/j.immuni.2016.02.024) Copyright © 2016 Elsevier Inc. Terms and Conditions

Figure 3 Heterogeneity of Tissue-Resident Macrophage Ontogeny in Adult Tissues in the Steady State Tissue-resident macrophages in closed tissues might arise only from YS macrophages (A, microglia), from both YS macrophages and fetal liver (FL) monocytes (B, Langerhans cells that have been shown to have a mixed contribution with around 20% of YS macrophages and 80% FL monocytes), or mostly from FL monocytes (C, alveolar macrophages and D, Kupffer cells). Note that for Kupffer cells, a minor contribution of neonatal monocytes and YS macrophages was suggested. For open tissues, bone marrow-derived monocytes are recruited and differentiate into macrophages with a kinetic specific to each tissue, with slow (heart and pancreas) and fast (gut and dermis) kinetics of replacement evidenced. Immunity 2016 44, 439-449DOI: (10.1016/j.immuni.2016.02.024) Copyright © 2016 Elsevier Inc. Terms and Conditions