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

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Abstract

Most haematopoietic cells renew from adult haematopoietic stem cells (HSCs)1,2,3, however, macrophages in adult tissues can self-maintain independently of HSCs4,5,6,7. Progenitors with macrophage potential in vitro have been described in the yolk sac before emergence of HSCs8,9,10,11,12,13, and fetal macrophages13,14,15 can develop independently of Myb4, a transcription factor required for HSC16, and can persist in adult tissues4,17,18. Nevertheless, the origin of adult macrophages and the qualitative and quantitative contributions of HSC and putative non-HSC-derived progenitors are still unclear19. 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.

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Figure 1: E8.5 Csf1r+ progenitors originate in the yolk sac and expand in the fetal liver.
Figure 2: E8.5 Csf1r+ progenitors differentiate into myeloid cells and red blood cells in the fetal liver.
Figure 3: Fetal liver HSC-derived Flt3+ progenitors give rise to monocytes and granulocytes in late embryos and adults but do not replace yolk-sac-derived macrophages.
Figure 4: Fetal macrophages and adult tissue-resident macrophages originate from Tie2-expressing progenitors before E10.5.

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Acknowledgements

The authors are indebted to J. Pollard, University of Edinburgh for the Csf1r reporter strains, J. Frampton, University of Birmingham for the Myb-deficient animals, and T. Boehm, Max Planck Institute, Freiburg for the Flt3Cre strain. The authors also thank A. McGuigan and the staff of the Biological Service Unit at King’s College London, S. Heck and the Biomedical Research Centre at King’s Health Partners, S. Woodcock and the staff of the Viapath haematology laboratory in Guy’s hospital and S. Schäfer and T. Arnsperger for technical assistance at the German Cancer Research Center. This work was supported by a Wellcome Trust Senior Investigator award (WT101853MA) and ERC Investigator award (2010-StG-261299) from the European Research Council to F.G. and an ERC Investigator award (Advanced Grant 233074), SFB 938 project L, and SFB 873 project B11 to H.-R.R.

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Authors and Affiliations

Authors

Contributions

E.G.P. and F.G. designed the study and wrote the manuscript. E.G.P., C.S., L.C., H.G. and C.T. performed fate-mapping experiments and E.G.P. and F.G. designed experiments and analysed the data. K.B. and H.-R.R. generated the Tie2MeriCreMer strain and K.K., K.B. and H.-R.R. designed, performed and analysed fate-mapping experiments. E.A. and E.G.P. performed the CFU assays and E.A., E.G.P., F.G. and M.F.d.B. analysed and interpreted the experimental data. All authors contributed to the manuscript.

Corresponding author

Correspondence to Frederic Geissmann.

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The authors declare no competing financial interests.

Extended data figures and tables

Extended Data Figure 1 Analysis of Csf1r reporter expression in fetal progenitor cells in Csf1riCre Rosa26YFP.

a, Schematic representation of the different haematopoietic and non-haematopoietic sites dissected in the mouse embryos: yolk sac (YS), aorta-gonado-mesonephros (AGM) region, fetal liver and head. b, Experimental design for fate-mapping analysis of Csf1r-expressing cells. Arrows indicate analysed time points c, Kit and CD45 expression on YFP+ cells from Csf1riCreRosa26YFP embryos (E8.25, n = 7; E8.5, n = 4; E9.25–E9.5, n = 16; E10.25, n = 9; E10.5, n = 5; E11.5, n = 8; E12.5, n = 5). d, Number of YFP+Kit+CD45lo cells per organ/region and developmental time points (mean ± s.e.m.) in Csf1riCreRosa26YFP embryos (upper panel). Number of YFP+AA4.1+Kit+CD45lo cells per embryonic region and developmental time points (mean ± s.e.m.) in Csf1riCre Rosa26YFP embryos (lower panel). e, AA4.1 and Kit expression on YFP+ cells from Csf1riCreRosa26YFP embryos (upper panel) and from Csf1rMeriCreMerRosa26YFP embryos pulsed with OH-TAM at E8.5 (lower panel).

Extended Data Figure 2 Fate-mapping analysis of Csf1r-expressing cells.

a, Experimental design for fate-mapping analysis of Csf1r-expressing cells. Arrows indicate analysed time points. b, YFP expression on live cells from Csf1rMeriCreMerRosa26YFP embryos pulsed at E6.5 with OH-TAM and analysed at E10.5 (n = 2) and E12.5 (n = 4). c, Percentage of YFP+ cells among Kit+CD45lo cells (YFP labelling efficiency) per organ/region (mean ± s.e.m.). Upper panel, Csf1riCreRosa26YFP embryos (E8.25, n = 7; E8.5, n = 4; E9.5, n = 16; E10.25, n = 9; E10.5, n = 5; E11.5, n = 8; E12.5, n = 5); lower panel, Csf1rMeriCreMerRosa26YFP embryos pulsed at E8.5 (E9.5, n = 3; E10.25, n = 3; E10.5, n = 4; E11.5, n = 4; E12.5, n = 9). d, Percentage of YFP+ cells among AA4.1+Kit+CD45lo cells (YFP labelling efficiency) per embryonic organ/region and developmental time points (mean ± s.e.m.). Upper panel, Csf1riCre Rosa26YFP embryos; lower panel, Csf1rMeriCreMerRosa26YFP embryos pulsed at E8.5.

Extended Data Figure 3 Csf1r+ progenitors have erythro-myeloid potential ex vivo.

a, Sorting strategy for CFU-C (colony forming unit-culture) assays for E9 Csf1riCreRosa26YFP yolk sac (upper panel) and E12.5 fetal liver from Csf1rMeriCreMerRosa26YFP embryos pulsed with OH-TAM at E8.5 (lower panel). Dead cells were excluded based on Hoechst 33258 incorporation and, after doublet exclusion, cells were gated based on CD45 and Kit expression. AA4.1+Kit+CD45lo and YFP+AA4.1+Kit+CD45lo cells were isolated from Cre and Cre+ embryos respectively. b, Mean CFU-C frequency from three independent experiments each of E9 Csf1riCreRosa26YFP YS and E12.5 fetal liver from Csf1rMeriCreMerRosa26YFP embryos pulsed with OH-TAM at E8.5. CFU-erythroid and/or megakaryocyte (E/Mk); CFU-granulocyte and/or monocyte/macrophage (G/M); CFU-mix, at least three of the following: G, E, M and Mk. c, Morphological validation of colony types obtained from E9 yolk sac Csf1riCre YFP+AA4.1+Kit+CD45lo CFU-C assays. Representative images from May-Grünwald-Giemsa stained cytospin preparations of mixed, E/Mk and G/M colonies. Black arrowhead, macrophages; granulocyte pathway, blue arrows; erythroid and megakaryocyte pathway, red arrows. Scale bar, 10 µm.

Extended Data Figure 4 Analysis of Csf1r reporter expression in fetal macrophages and red blood cells in Csf1riCreRosa26YFP embryos.

a, F4/80 and CD11b expression on YFP+ CD45+ from yolk sac, head (brain for E11.5), limbs and liver of Csf1riCreRosa26YFP embryos (E8.5, n = 4; E9.5, n = 16; E10.5, n = 5; E11.5, n = 9; E12.5, n = 5). Dashed line represents FMO (fluorescence minus one) control. b, Percentage of macrophages (F4/80bright) among YFP+ cells, mean ± s.e.m., in Csf1riCreRosa26YFP embryos (left) and in Csf1rMeriCreMer Rosa26YFP embryos pulsed with OH-TAM at E8.5 (right). See also Supplementary Table 1. c, Percentage of YFP+ cells among F4/80bright cells (YFP labelling efficiency) per embryonic organ/region and developmental time points (mean ± s.e.m.). Left panel, Csf1riCreRosa26YFP embryos (E8.25, n = 7; E8.5, n = 5; E9.5, n = 15; E10.25, n = 9; E10.5, n = 5; E11.5, n = 9; E12.5, n = 5); right panel: Csf1rMeriCreMerRosa26YFP embryos pulsed at E8.5 (E9.5, n = 3; E10.25, n = 3; E10.5, n = 4; E11.25, n = 4; E12.5, n = 9). d, YFP expression in erythrocytes (CD45Ter119+) from yolk sac and fetal liver of Csf1riCreRosa26YFP embryos (left) and Csf1rMeriCreMerRosa26YFP embryos pulsed with OH-TAM at E8.5 (right).

Extended Data Figure 5 Analysis of Flt3 reporter expression in blood leucocytes, stem/progenitor cells, fetal red blood cells, and adult liver, lung and spleen in Flt3CreRosa26YFP mice.

a, YFP labelling efficiency in blood lineages at different embryonic and adult time points (E14.5, n = 9; E16.5, n = 9; E18.5, n = 7; P8, n = 7; 4-week-old, n = 6; 12-week-old, n = 9; 40-week-old, n = 7) in Flt3CreRosa26YFP mice are shown. Lymphocytes were gated as CD3+/CD19+, granulocytes (CD11b+Gr1+CD115), Gr1+ monocytes (CD11b+Gr1+CD115+), Gr1 monocytes (CD11b+Gr1CD115+) and red blood cells (RBCs, CD45Ter119+). b, YFP labelling efficiency in bone marrow LT-HSCs, ST-HSCs, MPPs and LinSca1Kit+ progenitors in 4-week-old (n = 3) and 12-week-old (n = 6) Flt3CreRosa26YFP mice. c, YFP labelling efficiency in fetal liver red blood cell progenitors (CD45+Ter119+) and red blood cells (CD45Ter119+) in Flt3CreRosa26YFP mice (E14.5, n = 5; E16.5, n = 5; E18.5, n = 7), and comparison of YFP labelling efficiency in fetal liver and blood red blood cells in Flt3CreRosa26YFP mice at E14.5 (n = 5), E16.5 (n = 5) and E18.5 (n = 7). d, Expression of Gr1 and MHC II, Ly-6G and Siglec-F, CD11c and CD64, and Nkp46 and CD19 among F4/80loCD11bhi myeloid cells in the liver. Histograms represent Flt3Cre YFP labelling efficiency in the following defined populations: granulocytes (Gr1+MHC II or Ly-6G+), eosinophils (Siglec-F+), dendritic cells (CD11c+), B cells (CD19+) and NK cells (Nkp46+) (n = 3). e, Analysis of F4/80loCD11bhi myeloid cells in the lung as in b. f, Analysis of F4/80loCD11bhi myeloid cells in the spleen as in b. g, Expression of CD64 in F4/80bright macrophages and in F4/80lo myeloid cells in the liver, lung and spleen (FMO, fluorescence minus one).

Extended Data Figure 6 Characterization of fetal F4/80loCD11bhi myeloid cells in liver, lung and skin.

a, F4/80, Kit, CD11b and Gr1 expression on YFP+CD45+ cells in the fetal liver at E14.5 in Csf1rMeriCreMerRosa26YFP embryos pulsed at E8.5 (left panel). Representative images of May-Grünwald-Giemsa stained cytospin preparations of fetal liver YFP+F4/80bright and YFP+CD11bhi cells sorted from E14.5 Csf1rMeriCreMerRosa26YFP embryos pulsed with OH-TAM at E8.5 (right panel). Scale bar, 10 µm. b, c, F4/80, CD11b, Gr1 and Siglec F expression on CD45+ cells in the embryonic and post-natal lung (b) and skin (c) in Csf1rMeriCreMerRosa26YFP embryos pulsed with OH-TAM at E8.5 (green) and Flt3CreRosa26YFP embryos (orange). Representative images of May-Grünwald-Giemsa stained cytospin preparations of lung YFP+F4/80bright and YFP+CD11bhiF4/80lo (b) and skin YFP+F4/80bright and YFP+Kit+F4/80CD11b mast cells (c) sorted from E18.5 Flt3CreRosa26YFP embryos and E16.5 Csf1rMeriCreMerRosa26YFP embryos pulsed with OH-TAM at E8.5. Scale bar, 10 µm.

Extended Data Figure 7 Adult BM transplantation reconstitutes the haematopoietic system but does not replace tissue-resident F4/80bright macrophages.

a, Schematic representation of transplantation experiments. LT-HSCs isolated from bone marrow of panRosa26YFP donor mice were injected into Rag2−/−γc−/−KitW/Wv recipients (approximately 1,000 cells per recipient). Eight weeks after transplantation stem cells, myeloid progenitors, monocytes and macrophages of recipient mice were analysed for donor chimaerism. b, Long-term or short-term haematopoietic stem cells (LT-HSCs, ST-HSCs), multipotent progenitors (MPPs), common myeloid progenitors (CMPs), granulocyte-monocyte progenitors (GMPs), megakaryocyte-erythrocyte progenitors (MEPs), and circulating Ly6Chi and Ly6Clo monocytes were isolated from transplanted Rag2−/−γc−/−KitW/Wv mice and analysed for YFP expression. c, F4/80bright macrophages and F4/80lo myeloid cells in spleen, liver, lung, pancreas, epidermis and brain were analysed for YFP expression.

Extended Data Figure 8 Analysis of fetal stem/progenitor cells and fetal macrophages in Tie2MeriCreMerRosa26YFP embryos pulse-labelled from E6.5 to E10.5.

a, Experimental design for fate-mapping analysis of Tie2MeriCreMerRosa26YFP embryos pulse-labelled at E6.5, or E7.5, or E8.5, or E9.5 or E10.5. b, c, Representative flow cytometry of fetal liver stem/progenitor cells (b) and of fetal macrophages (c) in the yolk sac, head region, and embryo body at E12.5, injected at E6.5 or at E10.5. d, Representative images of May-Grünwald-Giemsa stained cytospin preparations of sorted YFP+ and YFP CD45+ F4/80bright macrophages of the embryo proper or the head region of E13.5 Tie2MeriCreMerRosa26YFP embryos pulsed at E7.5. Scale bar, 10 µm e, Quantification of the percentage of YFP+ stem/progenitor cells in the fetal liver and macrophages in yolk sac, brain (head) and embryo body at E12.5. Embryos were labelled at E6.5 (n = 5), or E7.5 (n = 7), or E8.5 (n = 4), or E9.5 (n = 5) or E10.5 (n = 7) and analysed at E12.5 (mean ± s.d.).

Extended Data Figure 9 Transplantation of YFP+ fetal liver LT-HSCs from Tie2MeriCreMerRosa26YFP into Rag2−/−γc−/−KitW/Wv mice.

a, Experimental design for pulse-labelling and LT-HSCs sort from Tie2MeriCreMerRosa26YFP embryos pulsed at E7.5. b, Fetal livers of E12.5 embryos pulsed at E7.5 were collected, YFP+LSK CD150+CD48LT-HSCs were sorted by flow cytometry and 10 LT-HSCs were injected into Rag2−/−γc−/−KitW/Wv recipients. c, Blood analysis of recipients 16 weeks after LT-HSC transplantation. Donor-derived (YFP+) and recipient-derived (YFP) blood cells were analysed for expression of CD19, CD3, CD11b, and Gr-1. One representative example is shown.

Extended Data Figure 10 Analysis of E9.5 YS progenitor cells in Tie2MeriCreMerRosa26YFP embryos pulse-labelled at E7.5.

a, Experimental design for fate-mapping analysis of Tie2-expressing cells in Tie2MeriCreMerRosa26YFP embryos. Embryonic cells were pulse-labelled by tamoxifen (TAM) administration into pregnant Tie2MeriCreMer mice at E7.5. Yolk sac (YS) and embryo proper (EP) of E9.5 Tie2MeriCreMerRosa26YFP embryos were analysed by flow cytometry. b, Quantification of total living cells and YFP+ living cells in yolk sac and embryo proper of analysed embryos (mean ± s.d., n = 5). c, Flow cytometry analysis of Kit+CD45lo cells among total living cells (black) or living YFP+ cells (blue) in yolk sac and embryo proper of a representative E9.5 Tie2MeriCreMerRosa26YFP embryo (left) and quantification of all analysed embryos (right; mean ± s.d., n = 5). d, Analysis of F4/80+ fetal macrophages among CD45+ cells (black) or YFP+CD45+ cells (blue) in yolk sac and embryo proper (mean ± s.d., n = 5) and quantification of all analysed embryos (right; mean ± s.d., n = 5). e, Percentage of YFP+ cells (YFP labelling efficiency) among live cells, Kit+ CD45lo, CD45+ Kit cells and F4/80+ cells from the yolk sac and embryo proper of E9.5 Tie2MeriCreMerRosa26YFP embryos pulsed at E7.5.

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Gomez Perdiguero, E., Klapproth, K., Schulz, C. et al. Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature 518, 547–551 (2015). https://doi.org/10.1038/nature13989

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