title: 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.
authors.affiliation: Centre for Molecular and Cellular Biology of Inflammation (CMCBI), King's College London, London SE1 1UL, UK.
authors.forename: Elisa
authors.initials: E
authors.lastname: Gomez Perdiguero
authors.affiliation: Division of Cellular Immunology, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany.
authors.forename: Kay
authors.initials: K
authors.lastname: Klapproth
authors.affiliation: Centre for Molecular and Cellular Biology of Inflammation (CMCBI), King's College London, London SE1 1UL, UK.
authors.forename: Christian
authors.initials: C
authors.lastname: Schulz
authors.affiliation: Division of Cellular Immunology, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Busch
authors.affiliation: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital University of Oxford, Oxford OX3 9DS, UK.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Azzoni
authors.affiliation: Centre for Molecular and Cellular Biology of Inflammation (CMCBI), King's College London, London SE1 1UL, UK.
authors.forename: Lucile
authors.initials: L
authors.lastname: Crozet
authors.affiliation: Centre for Molecular and Cellular Biology of Inflammation (CMCBI), King's College London, London SE1 1UL, UK.
authors.forename: Hannah
authors.initials: H
authors.lastname: Garner
authors.affiliation: Centre for Molecular and Cellular Biology of Inflammation (CMCBI), King's College London, London SE1 1UL, UK.
authors.forename: Celine
authors.initials: C
authors.lastname: Trouillet
authors.affiliation: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital University of Oxford, Oxford OX3 9DS, UK.
authors.forename: Marella F
authors.initials: MF
authors.lastname: de Bruijn
authors.affiliation: Centre for Molecular and Cellular Biology of Inflammation (CMCBI), King's College London, London SE1 1UL, UK.
authors.forename: Frederic
authors.initials: F
authors.lastname: Geissmann
authors.affiliation: Division of Cellular Immunology, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany.
authors.forename: Hans-Reimer
authors.initials: HR
authors.lastname: Rodewald
mesh_terms: D000818:Animals; D019070:Cell Lineage; D049109:Cell Proliferation; D058948:Cell Tracking; D004912:Erythrocytes / Q000166:cytology*; D005260:Female; D005333:Fetus / Q000166:cytology; D006098:Granulocytes / Q000166:cytology; D006410:Hematopoiesis; D007728:Kupffer Cells / Q000166:cytology; D007801:Langerhans Cells / Q000166:cytology; D008099:Liver / Q000166:cytology / Q000196:embryology; D008264:Macrophages / Q000166:cytology*; D016676:Macrophages, Alveolar / Q000166:cytology; D008297:Male; D051379:Mice; D017628:Microglia / Q000166:cytology; D009000:Monocytes / Q000166:cytology; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000378:metabolism; D042787:Receptor, TIE-2 / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology*; D015017:Yolk Sac / Q000166:cytology*; D051941:fms-Like Tyrosine Kinase 3 / Q000378:metabolism
chemical_list: C497971:Flt3 protein, mouse; D016186:Receptor, Macrophage Colony-Stimulating Factor; D042787:Receptor, TIE-2; C079086:Tek protein, mouse; D051941:fms-Like Tyrosine Kinase 3