Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors

Abstract

Most haematopoietic cells renew from adult haematopoietic stem cells (HSCs), however, macrophages in adult tissues can self-maintain independently of HSCs. Progenitors with macrophage potential in vitro have been described in the yolk sac before emergence of HSCs, and fetal macrophages can develop independently of Myb, a transcription factor required for HSC, and can persist in adult tissues. Nevertheless, the origin of adult macrophages and the qualitative and quantitative contributions of HSC and putative non-HSC-derived progenitors are still unclear. Here we show in mice that the vast majority of adult tissue-resident macrophages in liver (Kupffer cells), brain (microglia), epidermis (Langerhans cells) and lung (alveolar macrophages) originate from a Tie2(+) (also known as Tek) cellular pathway generating Csf1r(+) erythro-myeloid progenitors (EMPs) distinct from HSCs. EMPs develop in the yolk sac at embryonic day (E) 8.5, migrate and colonize the nascent fetal liver before E10.5, and give rise to fetal erythrocytes, macrophages, granulocytes and monocytes until at least E16.5. Subsequently, HSC-derived cells replace erythrocytes, granulocytes and monocytes. Kupffer cells, microglia and Langerhans cells are only marginally replaced in one-year-old mice, whereas alveolar macrophages may be progressively replaced in ageing mice. Our fate-mapping experiments identify, in the fetal liver, a sequence of yolk sac EMP-derived and HSC-derived haematopoiesis, and identify yolk sac EMPs as a common origin for tissue macrophages.

Pdgfrb‐Cre targets lymphatic endothelial cells of both venous and non‐venous origins

“…2c). Taken together, these results exclude the possibility that Pdgfrb‐Cre tracing of the lymphatic vasculature can be explained by a YS origin since the Pdgfrb‐Cre transgene cannot efficiently label YS HemECs or EMPs in E9 and E10 YS, nor can it trace early E10 monocytes and macrophages that are known to derive from the YS (Gomez Perdiguero et al, 2015; Hoeffel et al, 2015). …”

“…( D ) Gating scheme and representative data for E12 Pdgfrb‐Cre, R26‐mTmG YSs ( n  = 3), Dot plots as above (B and C). cKit+ population is adjusted for differences in PECAM1 expression between E9, E10 and E12 YS, to account for downregulation of vascular markers in late EMPs (Gomez Perdiguero et al ., 2015). Expression of Tomato and GFP in cKit + HemECs and EMPs is not displayed due to too low cell numbers of these cells at this stage.…”

“…For this purpose, we performed FACS analysis of Pdgfrb‐Cre;R26‐mTmG embryos at E10 (Fig. 2a), when the major pool of myeloid cells is YS‐derived (Gomez Perdiguero et al, 2015; Hoeffel et al, 2015). In three out of three embryos we could not find any tracing of YS‐derived monocytes and macrophages, defined by co‐expression of the pan‐myeloid marker CD11b and the pan‐leukocyte marker CD45 (Fig.…”

“…cKit is a marker associated with HemECs and HemEC‐derived hematopoietic progenitors from all known hemogenic sites of the embryo and the yolk sac (YS) (Antas et al ., 2013; Medvinsky et al, 2011). In the heart, Pdgfrb‐Cre induced labeling, together with positive labeling with Vav‐Cre , a pan‐hematopoietic lineage marker, and E7 induced Csf1r1‐MeriCreMer , which traces YS‐derived myeloid cells (Gomez Perdiguero et al, 2015; Hoeffel et al, 2015), was proposed to indicate YS HemEC as the source of cardiac LECs (Klotz et al, 2015). …”

Gene regulatory mechanisms underlying the intestinal innate immune response

“…In the steady state, they arise from two distinct sources: first, continuously recruited from circulating monocytes in the gut [10], the dermis [11] and the heart [12], and second, from fetal monocytes and yolk sac precursors that colonize the whole embryo between E8.5 and E10.5, becoming self-renewal differentiated tissue-resident macrophages [13,14,15 ]. Similar to other systems such as mammalian forebrain, heart and liver [16] as well as cells that arise from hematopoiesis [17 ], macrophage development involves substantial reorganization of the chromatin landscape [6 ,7 ].…”