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

Partha Dutta, Friedrich Felix Hoyer, Lubov S. Grigoryeva, Hendrik B. Sager, Florian Leuschner, Gabriel Courties, Anna Borodovsky, Tatiana Novobrantseva, Vera M. Ruda, Kevin Fitzgerald, Yoshiko Iwamoto, Gregory Wojtkiewicz, Yuan Sun, Nicolas Da Silva, Peter Libby, Daniel G. Anderson, Filip K. Swirski, Ralph Weissleder, Matthias Nahrendorf

Research output: Contribution to journalArticlepeer-review

127 Scopus citations

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.

Original languageEnglish
Pages (from-to)497-512
Number of pages16
JournalJournal of Experimental Medicine
Volume212
Issue number4
DOIs
StatePublished - 6 Apr 2015
Externally publishedYes

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