title: Macrophages retain hematopoietic stem cells in the spleen via VCAM-1.
abstract: Splenic myelopoiesis provides a steady flow of leukocytes to inflamed tissues, and leukocytosis correlates with cardiovascular mortality. Yet regulation of hematopoietic stem cell (HSC) activity in the spleen is incompletely understood. Here, we show that red pulp vascular cell adhesion molecule 1 (VCAM-1)(+) macrophages are essential to extramedullary myelopoiesis because these macrophages use the adhesion molecule VCAM-1 to retain HSCs in the spleen. Nanoparticle-enabled in vivo RNAi silencing of the receptor for macrophage colony stimulation factor (M-CSFR) blocked splenic macrophage maturation, reduced splenic VCAM-1 expression and compromised splenic HSC retention. Both, depleting macrophages in CD169 iDTR mice or silencing VCAM-1 in macrophages released HSCs from the spleen. When we silenced either VCAM-1 or M-CSFR in mice with myocardial infarction or in ApoE(-/-) mice with atherosclerosis, nanoparticle-enabled in vivo RNAi mitigated blood leukocytosis, limited inflammation in the ischemic heart, and reduced myeloid cell numbers in atherosclerotic plaques.
authors: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114 mnahrendorf@mgh.harvard.edu dutta.partha@mgh.harvard.edu.
authors: Partha
authors: P
authors: Dutta
authors: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114.
authors: Friedrich Felix
authors: FF
authors: Hoyer
authors: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114.
authors: Lubov S
authors: LS
authors: Grigoryeva
authors: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114.
authors: Hendrik B
authors: HB
authors: Sager
authors: Department of Cardiology, Medical University Hospital Heidelberg, D-69120 Heidelberg, Germany DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, D-69120 Heidelberg, Germany.
authors: Florian
authors: F
authors: Leuschner
authors: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114.
authors: Gabriel
authors: G
authors: Courties
authors: Alnylam Pharmaceuticals, Cambridge, MA 02142.
authors: Anna
authors: A
authors: Borodovsky
authors: Alnylam Pharmaceuticals, Cambridge, MA 02142.
authors: Tatiana
authors: T
authors: Novobrantseva
authors: Alnylam Pharmaceuticals, Cambridge, MA 02142.
authors: Vera M
authors: VM
authors: Ruda
authors: Alnylam Pharmaceuticals, Cambridge, MA 02142.
authors: Kevin
authors: K
authors: Fitzgerald
authors: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114.
authors: Yoshiko
authors: Y
authors: Iwamoto
authors: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114.
authors: Gregory
authors: G
authors: Wojtkiewicz
authors: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114.
authors: Yuan
authors: Y
authors: Sun
authors: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114.
authors: Nicolas
authors: N
authors: Da Silva
authors: Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115.
authors: Peter
authors: P
authors: Libby
authors: David H. Koch Institute for Integrative Cancer Research, Department of Chemical Engineering, and Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02142 David H. Koch Institute for Integrative Cancer Research, Department of Chemical Engineering, and Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02142 David H. Koch Institute for Integrative Cancer Research, Department of Chemical Engineering, and Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02142 Division of Health Science Technology, Harvard University and Massachusetts Institute of Technology, Cambridge, MA 02139.
authors: Daniel G
authors: DG
authors: Anderson
authors: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114.
authors: Filip K
authors: FK
authors: Swirski
authors: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114 Department of Systems Biology, Harvard Medical School, Boston, MA 02115.
authors: Ralph
authors: R
authors: Weissleder
authors: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114 mnahrendorf@mgh.harvard.edu dutta.partha@mgh.harvard.edu.
authors: Matthias
authors: M
authors: Nahrendorf
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000276:immunology; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D006411:Hematopoiesis, Extramedullary / Q000235:genetics / Q000276:immunology*; D006412:Hematopoietic Stem Cells / Q000276:immunology* / Q000473:pathology; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D038042:Myelopoiesis / Q000235:genetics / Q000276:immunology*; D009203:Myocardial Infarction / Q000235:genetics / Q000276:immunology / Q000473:pathology; D053758:Nanoparticles; D058226:Plaque, Atherosclerotic / Q000235:genetics / Q000276:immunology / Q000473:pathology; D034622:RNA Interference; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology; D063267:Sialic Acid Binding Ig-like Lectin 1 / Q000235:genetics / Q000276:immunology; D013154:Spleen / Q000276:immunology* / Q000473:pathology; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000276:immunology*
chemical_list: D001057:Apolipoproteins E; D063267:Sialic Acid Binding Ig-like Lectin 1; C571167:Siglec1 protein, mouse; D019010:Vascular Cell Adhesion Molecule-1; D016186:Receptor, Macrophage Colony-Stimulating Factor