C-Myb+ Erythro-Myeloid Progenitor-Derived Fetal Monocytes Give Rise to Adult Tissue-Resident Macrophages

Abstract

Summary Although classified as hematopoietic cells, tissue- resident macrophages (MFs) arise from embryonic precursors that seed the tissues prior to birth to generate a self-renewing population, which is maintained independently of adult hematopoiesis. Here we reveal the identity of these embryonic precursors using an in utero MF-depletion strategy and fate-mapping of yolk sac (YS) and fetal liver (FL) hematopoiesis. We show that YS MFs are the main precursors of microglia, while most other MFs derive from fetal monocytes (MOs). Both YS MFs and fetal MOs arise from erythro-myeloid progenitors (EMPs) generated in the YS. In the YS, EMPs gave rise to MFs without monocytic intermediates, while EMP seeding the FL upon the establishment of blood circulation acquired c-Myb expression and gave rise to fetal MOs that then seeded embryonic tissues and differentiated into MFs. Thus, adult tissue- resident MFs established from hematopoietic stem cell-independent embryonic precursors arise from two distinct developmental programs.

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). …”

“…1A) (Gomez Perdiguero E et al, 2015; Hoeffel et al, 2015; Medvinsky et al, 2011). The R26‐mTmG reporter allows detection of Cre activity by the recombination‐induced expression of membrane‐bound green fluorescent protein (GFP) and inactivation of the red fluorescent protein Tomato expression (Muzumdar et al, 2007).…”

“…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.…”

TGF-β1 modulates microglial phenotype and promotes recovery after intracerebral hemorrhage

“…It has recently been shown, however, that unlike blood-derived macrophages, microglia derive from yolk sac erythromyeloid progenitors. Microglia develop independently of the transcription factor c-Myb and hematopoietic stem cells (5,6) but are dependent upon the transcription factors IRF8 and PU.1 (7). Microglia also have a unique molecular signature that is distinct from that of bloodderived macrophages (8,9).…”

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 ].…”