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

doi:10.1038/nature13989

. 2015 Feb 26;518(7540):547-51.

doi: 10.1038/nature13989. Epub 2014 Dec 3.

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

Affiliations

¹ Centre for Molecular and Cellular Biology of Inflammation (CMCBI), King's College London, London SE1 1UL, UK.
² Division of Cellular Immunology, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany.
³ MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital University of Oxford, Oxford OX3 9DS, UK.

PMID: 25470051
PMCID: PMC5997177
DOI: 10.1038/nature13989

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

Elisa Gomez Perdiguero et al. Nature. 2015.

. 2015 Feb 26;518(7540):547-51.

doi: 10.1038/nature13989. Epub 2014 Dec 3.

Affiliations

¹ Centre for Molecular and Cellular Biology of Inflammation (CMCBI), King's College London, London SE1 1UL, UK.
² Division of Cellular Immunology, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany.
³ MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital University of Oxford, Oxford OX3 9DS, UK.

PMID: 25470051
PMCID: PMC5997177
DOI: 10.1038/nature13989

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.

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Conflict of interest statement

The authors declare no competing financial interests.

Figures

**Extended Data Figure 1. Analysis of *Csf1r* reporter expression in fetal progenitor cells in *Csf1r^iCre Rosa26^YFP*.**
a, Schematic representation of the different hematopoietic and non-hematopoietic 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 *Csf1r^iCre Rosa26^YFP* 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⁺ CD45^low cells per organ/region and developmental time points (mean±s.e.m.) in *Csf1r^iCre Rosa26^YFP* embryos (upper panel). Number of YFP⁺ AA4.1⁺ Kit⁺ CD45^low cells per embryonic region and developmental time points (mean±s.e.m.) in *Csf1r^iCre Rosa26^YFP* embryos (lower panel). e, AA4.1 and Kit expression on YFP⁺ cells from *Csf1r^iCre Rosa26^YFP* embryos (upper panel) and from *Csf1r^MeriCreMer Rosa26^YFP* 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 *Csf1r^MeriCreMer Rosa26^YFP* 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⁺ CD45^low cells (YFP labelling efficiency) per organ/region (mean±s.e.m.). Upper panel, *Csf1r^iCre Rosa26^YFP* 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 *Csf1r^MeriCreMer Rosa26^YFP* 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). e, Percentage of YFP⁺ cells among AA4.1⁺ Kit⁺ CD45^low cells (YFP labelling efficiency) per embryonic organ/region and developmental time points (mean±s.e.m.). Upper panel, *Csf1r^iCre Rosa26^YFP* embryos; lower panel: *Csf1r^MeriCreMer Rosa26^YFP* 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 *Csf1r^iCre Rosa26^YFP* YS (upper panel) and E12.5 fetal liver from *Csf1r^MeriCreMer Rosa26^YFP* 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⁺ CD45^low and YFP⁺ AA4.1⁺ Kit⁺ CD45^low cells were isolated from Cre^- and Cre⁺ embryos respectively. b, Mean CFU-C (colony forming unit-culture) frequency from three independent experiments each of E9 *Csf1r^iCre Rosa26^YFP* YS and E12.5 fetal liver from *Csf1r^MeriCreMer Rosa26^YFP* 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 YS *Csf1r^iCre* YFP⁺ AA4.1⁺ Kit⁺ CD45^low 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, 10μm.

**Extended Data Figure 4. Analysis of *Csf1r* reporter expression in fetal macrophages and red blood cells in *Csf1r^iCre Rosa26^YFP*.**
a, F4/80 and CD11b expression on YFP⁺ CD45⁺ from YS, head (brain for E11.5), limbs and liver of *Csf1r^iCre Rosa26^YFP* embryos (E8.5, n=4; E9.5, n=16; E10.5, n=5; E11.5, n=9; E12.5, n=5). Dashed line represent FMO (fluorescence minus one) control. b, Percentage of macrophages (F4/80^bright) among YFP⁺ cells, mean±s.e.m., in *Csf1r^iCre Rosa26^YFP* embryos (left) and *Csf1r^MeriCreMer Rosa26^YFP* embryos pulsed with OH-TAM at E8.5 (right). See also Extended Data Table 1. c, Percentage of YFP⁺ cells among F4/80^bright cells (YFP labelling efficiency) per embryonic organ/region and developmental time points (mean±s.e.m.). Left panel, *Csf1r^iCre Rosa26^YFP* 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: *Csf1r^MeriCreMer Rosa26^YFP* 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 (CD45^- Ter119⁺) from YS and fetal liver of *Csf1r^iCre Rosa26^YFP* embryos (left) and *Csf1r^MeriCreMer Rosa26^YFP* 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 *Flt3^Cre Rosa26^YFP 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 *Flt3^Cre Rosa26^YFP* mice are shown. Lymphocytes were gated as CD3⁺/CD19⁺, Granulocytes (CD11b⁺ Gr1⁺ CD115^-), Gr1⁺ monocytes (CD11b⁺ Gr1⁺ CD115⁺), Gr1^- monocytes (CD11b⁺ Gr1^- CD115⁺) and Red Blood Cells (RBCs, CD45^- Ter119⁺). b, YFP labelling efficiency in bone marrow LT-HSC, ST-HSC, MPP and Lin^- Sca1^- Kit⁺ progenitors in 4 (n=3) and 12 week-old (n=6) *Flt3^Cre Rosa26^YFP* mice. c, YFP labelling efficiency in fetal liver RBC progenitors (CD45⁺ Ter119⁺) and RBCs (CD45^- Ter119⁺) in *Flt3^Cre Rosa26^YFP* mice (E14.5, n=5; E16.5, n=5; E18.5, n=7) and comparison of YFP labelling efficiency in fetal liver and blood RBCs in *Flt3^Cre Rosa26^YFP* 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 F4/80^low CD11b^high myeloid cells in the liver. Histograms represent *Flt3^Cre* 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 F4/80^low CD11b^high myeloid cells in the lung as in (b). f, Analysis of F4/80^low CD11b^high myeloid cells in the spleen as in (b). g, Expression of CD64 in F4/80^bright macrophages and F4/80^low myeloid cells in the liver, lung and spleen (FMO, Fluorescence minus one).

**Extended Data Figure 6. Characterisation of fetal F4/80^low CD11b^high 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 *Csf1r^MeriCreMer Rosa26^YFP* embryos pulsed at E8.5 (left panel). Representative images of May-Grünwald-Giemsa stained cytospin preparations of fetal liver YFP⁺ F4/80^bright and YFP⁺ CD11b^high cells sorted from E14.5 *Csf1r^MeriCreMer Rosa26^YFP* embryos pulsed with OH-TAM at E8.5 (right panel). Scale bar,10μm. **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 *Csf1r^MeriCreMer Rosa26^YFP* embryos pulsed with OH-TAM at E8.5 (green) and *Flt3^Cre Rosa26^YFP* embryos (orange). Representative images of May-Grünwald-Giemsa stained cytospin preparations of lung YFP⁺ F4/80^bright and YFP⁺ CD11b^high F4/80^low (b) and skin YFP⁺ F4/80^bright and YFP⁺ Kit⁺ F4/80^- CD11b^- mast cells (c) sorted from E18.5 *Flt3^Cre Rosa26^YFP* embryos and E16.5 *Csf1r^MeriCreMer Rosa26^YFP* embryos pulsed with OH-TAM at E8.5. Scale bar 10μm.

**Extended Data Figure 7. Adult BM transplantation reconstitutes the hematopoietic system but does not replace tissue resident F4/80^bright macrophages.**
a, Schematic representation of transplantation experiments. LT-HSC isolated from bone marrow of *panRosa26^YFP* donor mice were injected into *Rag2^-/-γ_c^-/-* *Kit^W/Wv* recipients (approx. 1000 cells/recipient). Eight weeks after transplantation stem cells, myeloid progenitors, monocytes and macrophages of recipient mice were analysed for donor chimerism. b, Long-term or short-term hematopoietic stem cells (LT-HSC, ST-HSC), multipotent progenitors (MPP), common myeloid progenitors (CMP), granulocyte-monocyte progenitors (GMP), megakaryocyte-erythrocyte progenitors (MEP), and circulating Ly6C^hi and Ly6C^lo monocytes were isolated from transplanted *Rag2^-/-γ_c^-/-Kit^W/Wv* mice and analysed for YFP expression. c, F4/80^bright macrophages and F4/80^low 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 *Tie2^MeriCreMer Rosa26^YFP* embryos pulse-labelled from E6.5 to E10.5.**
a, Experimental design for fate mapping analysis of *Tie2^MeriCreMerRosa26^YFP* 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⁺ F4/80^bright macrophages of the embryo proper or the head region of E13.5 *Tie2^MeriCreMerRosa26^YFP* embryos pulsed at E7.5. Scale bar, 10μm 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), 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-HSC from *Tie2^MeriCreMerRosa26^YFP* into *Rag2^-/- γ_c^-/-Kit^W/Wv* mice.**
a, Experimental design for pulse-labelling and LT-HSC sort from *Tie2^MeriCreMerRosa26^YFP* embryos pulsed at E7.5. b, Fetal livers of E12.5 embryos pulsed at E7.5 were harvested, YFP⁺ LSK CD150⁺CD48^- LT-HSC were sorted by flow cytometry and 10 LT-HSC were injected into *Rag2^-/-γ_c^-/-Kit^W/Wv* recipients. c, Blood analysis of recipients 16 week 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 *Tie2^MeriCreMer Rosa26^YFP* embryos pulse-labelled at E7.5.**
a, Experimental design for fate mapping analysis of *Tie2*-expressing cells in *Tie2^MeriCreMerRosa26^YFP* embryos. Embryonic cells were pulse-labelled by Tamoxifen (TAM) administration into pregnant *Tie2^MeriCreMer* mice at E7.5. Yolk sac (YS) and embryo proper (EP) of E9.5 *Tie2^MeriCreMerRosa26^YFP* embryos were analysed by flow cytometry. b, Quantification of total living cells and YFP⁺ living cells in YS and EP of analysed embryos (mean±s.d., n=5). c, Flow cytometry analysis of Kit⁺ CD45^low cells among total living cells (black) or living YFP⁺ cells (blue) in YS and EP of a representative E9.5 *Tie2^MeriCreMerRosa26^YFP* 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 YS and EP (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⁺ CD45^low, CD45⁺ Kit^- cells and F4/80⁺ cells from the YS and EP of E9.5 *Tie2^MeriCreMerRosa26^YFP* embryos pulsed at E7.5.

**Figure 1. E8.5 *Csf1r*⁺ progenitors originate in the yolk sac and expand in the fetal liver.**
a, Fate-mapping analysis of *Csf1r*-expressing cells. Arrows indicate time points for analysis, and green shades the genetic labelling period. b, YFP expression on live cells from *Csf1r^iCre Rosa26^YFP* yolk sac (YS), separated by somite pairs between E8.25 and E9 (0sp, n=3; 3/6sp, n=3; 7-9sp, n=5; 11-13sp, n=3; 16-18sp, n=4; 20-25sp, n=4) (upper panels), and Kit and CD45 expression on YFP⁺ cells (lower panels). R1 indicates Kit⁺ CD45^low, and R2 indicates Kit^- CD45⁺ cells. c, Schematic representation of sites analysed in mouse embryos: YS, AGM region, fetal liver and head. Kit and CD45 phenotype of YFP⁺ cells from *Csf1r^MeriCreMer Rosa26^YFP* embryos pulsed with OH-TAM at E8.5 (E9.5, n=3; E10.25, n=3; E10.5, n=4; E11.25, n=4; E12.5, n=9). d, Number of YFP⁺ Kit⁺ CD45^low cells (R1 in panel b) per organ or region (mean ± s.e.m.) in *Csf1r^MeriCreMer Rosa26^YFP* embryos pulsed at E8.5. e, Number of YFP⁺ AA4.1⁺ Kit⁺ CD45^low cells per embryonic region and time points (mean ± s.e.m.) in *Csf1r^MeriCreMer Rosa26^YFP* embryos pulsed at E8.5. See also Supplementary Table 1 and Extended Data Figs. 1 and 2.

**Figure 2. E8.5 *Csf1r*⁺ progenitors differentiate into myeloid cells and red blood cells in the fetal liver.**
a, Distribution of mixed (Mix), G/M, and E/Mk CFU-C from unsorted, AA4.1⁺ Kit⁺ CD45^low and YFP⁺ AA4.1⁺ Kit⁺ CD45^low cells from E9 YS from *Csf1r^iCre Rosa26^YFP* and E12.5 fetal liver from *Csf1r^MeriCreMer Rosa26^YFP* embryos pulsed with OH-TAM at E8.5 (three independent experiments each). 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. See also Extended Data Fig. 3. b, F4/80 and CD11b expression on YFP⁺ CD45⁺ from YS, head (brain for E11.5), limbs and liver of *Csf1r^MeriCreMer Rosa26^YFP* embryos pulsed with OH-TAM at E8.5 and analysed on E9.5 (n=3), E10.5 (n=4), E11.5 (n=4), and E12.5 (n=9); Dashed lines represent FMO (fluorescence minus one) control. See also Extended Data Fig. 4. c, F4/80, CD11b, Gr1, Ly-6G and Ly-6C expression in fetal liver CD45⁺ YFP⁺ cells from *Csf1r^MeriCreMer Rosa26^YFP* embryos pulse-labelled at E8.5, and analysed on E12.5 (n=9) and E16.5 (n=14). May-Grünwald-Giemsa stained cytospin preparations of fetal liver YFP⁺ F4/80^bright and YFP⁺ CD11b^high cells sorted from E16.5 *Csf1r^MeriCreMer Rosa26^YFP* embryos pulsed with OH-TAM at E8.5. See also Extended Data Fig. 6a for sorted cells from E14.5 *Csf1r^MeriCreMer* embryos. Scale bar, 10μm. d, YFP labelling efficiency (%) among red blood cells in fetal liver from *Csf1r^MeriCreMer Rosa26^YFP* embryos pulsed with OH-TAM at E8.5, mean ± s.e.m. (E11.5, n=4; E12.5, n=9; E14.5, n=5; E16.5, n=11; E18.5, n=4).

**Figure 3. Fetal liver HSC-derived *Flt3*⁺ progenitors give rise to monocytes and granulocytes in late embryos and adults but do not replace YS-derived macrophages.**
a, F4/80, Kit, CD11b and Gr1 expression on total CD45⁺ cells (black) and YFP⁺ CD45⁺ cells from *Csf1r^MeriCreMer Rosa26^YFP* embryos pulsed at E8.5 (green) in the FL at the indicated days of embryonic development (E14.5, n=5; E16.5, n= 10; E18.5, n=9). F4/80, Kit, CD11b and Gr1 expression on YFP⁺ CD45⁺ cells from *Flt3^Cre Rosa26^YFP* embryos (orange) (E14.5, n=7; E16.5, n=6; E18.5, n=6). F4/80 and CD11b expression on CD45⁺ cells in *Myb^-/-* embryos (E14.5, n=4; E16.5, n= 7). b, YFP labelling efficiency in Kit⁺ lin^- cells, CD11b^high F4/80^low cells (characterised in Extended Data Fig. 5) and F4/80^bright macrophages (Kupffer cells in adults) in fetal and adult *Flt3^Cre Rosa26^YFP* liver (first panel on the left). YFP labelling efficiency in blood monocytes, brain microglia (CD45^low F4/80⁺) and CD45⁺ F4/80⁺ brain macrophages in *Flt3^Cre Rosa26^YFP* pups and mice (second panel). YFP labelling efficiency in alveolar macrophages (F4/80^bright Siglec-F⁺ CD11b^-) and F4/80^low CD11b^high myeloid cells in *Flt3^Cre Rosa26^YFP* lungs (third panel). YFP labelling efficiency in epidermal Langerhans cells (LCs) and dermal CD11b^high (MHC II⁺ EpCAM^-) myeloid cells in *Flt3^Cre Rosa26^YFP* skin (fourth panel). See Extended Data Fig. 6b and c. Mean ± s.e.m.; P8, n=3; 4-week-old, n=6; 12-week-old, n=11-14; 40-week-old, n=7; 1-year-old, n=3).w, week; y, year. c, Representative images of May-Grünwald-Giemsa stained cytospin preparations of YFP⁺ CD11b^high F4/80^low cells sorted from E18.5 *Flt3^Cre Rosa26^YFP* fetal liver. Scale bar, 10μm.

**Figure 4. Fetal macrophages and adult tissue-resident macrophages originate from *Tie2*-expressing progenitors prior to E10.5.**
a, Fate mapping analysis of *Tie2*-expressing cells after tamoxifen (TAM) administration at E7.5, or E8.5, or E9.5 or E10.5. Arrows indicate time points for analysis. b, Flow cytometric analysis of fetal liver long-term or short-term hematopoietic stem cells (LT-HSCs, ST-HSCs), multipotent progenitors (MPPs), common myeloid progenitors (CMPs), granulocyte-monocyte progenitors (GMPs), megakaryocyte-erythrocyte progenitors (MEPs) (left panel) and of fetal macrophages (right panel) in the yolk sac, brain, and fetal liver. Time points of labelling (E7.5 (n=7); E10.5 (n=7)) and analysis are indicated, and for each experiment one representative analysis is shown. See Extended Data Fig. 8 for quantitative analysis. c, Frequencies of labelled HSCs and progenitor cells, splenocytes, and F4/80^low CD11b^high myeloid cells and F4/80^bright resident macrophages in spleen, liver lung, epidermis and brain were analysed (mean ± s.d.) from 6-8-week-old *Tie2^MeriCreMer* animals pulse-labelled at E7.5 (n=4), E8.5 (n=4), E9.5 (n=4) or E10.5 (n=6).

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[1] Orkin SH, Zon LI. Hematopoiesis: an evolving paradigm for stem cell biology. Cell. 2008;132:631–644. doi: 10.1016/j.cell.2008.01.025. - DOI - PMC - PubMed

[2] Orkin SH, Zon LI. Hematopoiesis: an evolving paradigm for stem cell biology. Cell. 2008;132:631–644. doi: 10.1016/j.cell.2008.01.025. - DOI - PMC - PubMed

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

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

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