title: Primitive Embryonic Macrophages are Required for Coronary Development and Maturation.
abstract: It is now recognized that macrophages residing within developing and adult tissues are derived from diverse progenitors including those of embryonic origin. Although the functions of macrophages in adult organisms are well studied, the functions of macrophages during organ development remain largely undefined. Moreover, it is unclear whether distinct macrophage lineages have differing functions.
  
  
  
  To address these issues, we investigated the functions of macrophage subsets resident within the developing heart, an organ replete with embryonic-derived macrophages.
  
  
  
  Using a combination of flow cytometry, immunostaining, and genetic lineage tracing, we demonstrate that the developing heart contains a complex array of embryonic macrophage subsets that can be divided into chemokine (C-C motif) receptor 2(-) and chemokine (C-C motif) receptor 2(+) macrophages derived from primitive yolk sac, recombination activating gene 1(+) lymphomyeloid, and Fms-like tyrosine kinase 3(+) fetal monocyte lineages. Functionally, yolk sac-derived chemokine (C-C motif) receptor 2(-) macrophages are instrumental in coronary development where they are required for remodeling of the primitive coronary plexus. Mechanistically, chemokine (C-C motif) receptor 2(-) macrophages are recruited to coronary blood vessels at the onset of coronary perfusion where they mediate coronary plexus remodeling through selective expansion of perfused vasculature. We further demonstrate that insulin like growth factor signaling may mediate the proangiogenic properties of embryonic-derived macrophages.
  
  
  
  Together, these findings demonstrate that the embryonic heart contains distinct lineages of embryonic macrophages with unique functions and reveal a novel mechanism that governs coronary development.
authors.affiliation: From the Center for Cardiovascular Research, Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, MO (J.L., K.J.L.); Haematopoietic Stem Cell Biology Laboratory, MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Headington, Oxford, United Kingdom (J.C., H.B., S.E.W.J.); Peter Munk Cardiac Centre, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada (S.E.); and Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO (K.J.L.).
authors.forename: Jamison
authors.initials: J
authors.lastname: Leid
authors.affiliation: From the Center for Cardiovascular Research, Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, MO (J.L., K.J.L.); Haematopoietic Stem Cell Biology Laboratory, MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Headington, Oxford, United Kingdom (J.C., H.B., S.E.W.J.); Peter Munk Cardiac Centre, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada (S.E.); and Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO (K.J.L.).
authors.forename: Joana
authors.initials: J
authors.lastname: Carrelha
authors.affiliation: From the Center for Cardiovascular Research, Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, MO (J.L., K.J.L.); Haematopoietic Stem Cell Biology Laboratory, MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Headington, Oxford, United Kingdom (J.C., H.B., S.E.W.J.); Peter Munk Cardiac Centre, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada (S.E.); and Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO (K.J.L.).
authors.forename: Hanane
authors.initials: H
authors.lastname: Boukarabila
authors.affiliation: From the Center for Cardiovascular Research, Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, MO (J.L., K.J.L.); Haematopoietic Stem Cell Biology Laboratory, MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Headington, Oxford, United Kingdom (J.C., H.B., S.E.W.J.); Peter Munk Cardiac Centre, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada (S.E.); and Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO (K.J.L.).
authors.forename: Slava
authors.initials: S
authors.lastname: Epelman
authors.affiliation: From the Center for Cardiovascular Research, Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, MO (J.L., K.J.L.); Haematopoietic Stem Cell Biology Laboratory, MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Headington, Oxford, United Kingdom (J.C., H.B., S.E.W.J.); Peter Munk Cardiac Centre, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada (S.E.); and Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO (K.J.L.).
authors.forename: Sten E W
authors.initials: SE
authors.lastname: Jacobsen
authors.affiliation: From the Center for Cardiovascular Research, Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, MO (J.L., K.J.L.); Haematopoietic Stem Cell Biology Laboratory, MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Headington, Oxford, United Kingdom (J.C., H.B., S.E.W.J.); Peter Munk Cardiac Centre, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada (S.E.); and Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO (K.J.L.). klavine@dom.wustl.edu.
authors.forename: Kory J
authors.initials: KJ
authors.lastname: Lavine
mesh_terms: D000818:Animals; D000073883:CX3C Chemokine Receptor 1; D019070:Cell Lineage; D002478:Cells, Cultured; D006321:Heart / Q000196:embryology*; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D015017:Yolk Sac / Q000166:cytology / Q000378:metabolism; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics / Q000378:metabolism
chemical_list: D000073883:CX3C Chemokine Receptor 1; C000604004:Csf1r protein, mouse; C471885:Cx3cr1 protein, mouse; D019707:Receptors, Chemokine; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3
keywords: flow cytometry; fms-like tyrosine kinase 3; macrophages; monocytes; yolk sac