Macrophages retain hematopoietic stem cells in the spleen via VCAM-1.
Bottom Line: Yet regulation of hematopoietic stem cell (HSC) activity in the spleen is incompletely understood.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.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.
Affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114 firstname.lastname@example.org email@example.com.Show MeSH
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Mentions: Because VCAM-1 was the only retention factor that changed in the spleen after M-CSFR knockdown (Fig. 3 D), we investigated which splenocytes express VCAM-1. We found that splenic macrophages (Ulyanova et al., 2005) and endothelial cells express VCAM-1 at high levels (Fig. 5, A and B). We next tested whether splenic HSCs reside close to VCAM-1–expressing cells. Toward this end, we transferred GFP+ HSPCs (LSKs) into LPS-primed mice and imaged splenic sections 3 d later. Transferred GFP+ progenitors localized in numerous splenic locations and formed colonies in the red pulp, indicating their proliferation (Fig. 5 C). GFP+ colonies localized near VCAM-1+ macrophages (Fig. 5 D). Numerous GFP+ cells closely contacted VCAM-1–expressing macrophages in the splenic red pulp (Fig. 5, E and F; and Video 1). Indeed, 44.4 ± 3.7% of GFP+ cells lay in direct contact with or <1 µm distant from VCAM-1+ macrophages (Fig. 5 G). Another 49.4 ± 3.1% of the HSPCs resided within 1–10 µm of VCAM-1+ macrophages.
Affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114 firstname.lastname@example.org email@example.com.