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J Exp Med. 2015 Apr 6;212(4):497-512. doi: 10.1084/jem.20141642. Epub 2015 Mar 23.

Macrophages retain hematopoietic stem cells in the spleen via VCAM-1.

Author information

1
Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114 mnahrendorf@mgh.harvard.edu dutta.partha@mgh.harvard.edu.
2
Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114.
3
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.
4
Alnylam Pharmaceuticals, Cambridge, MA 02142.
5
Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115.
6
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.
7
Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114 Department of Systems Biology, Harvard Medical School, Boston, MA 02115.

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.

PMID:
25800955
PMCID:
PMC4387283
DOI:
10.1084/jem.20141642
[Indexed for MEDLINE]
Free PMC Article

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