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 email@example.com firstname.lastname@example.org.Show MeSH
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Mentions: Our data suggest that splenic macrophages retain progenitors via expression of the adhesion molecule VCAM-1. To test this hypothesis directly, we formulated siRNA that targets VCAM-1 within macrophage-avid lipidoid nanoparticles (sense, AcuGGGuuGAcuuucAGGudTsdT; anti-sense, ACCUGAAAGUcAACCcAGUdTsdT). This treatment, which limited VCAM-1 protein concentrations in macrophages but not in endothelial cells (Fig. 6 A), reduced splenic progenitor retention (Fig. 6 B). In contrast, numbers of HSCs, LSKs, and GMPs increased significantly in the circulation (Fig. 6 C), indicating mobilization of these cells into the blood after VCAM-1 knockdown in macrophages. In the bone marrow, HSPC numbers did not change significantly after VCAM-1 knockdown in macrophages (Fig. 6 D), pointing to retention mechanisms that compensate for reduced VCAM-1 levels in the bone marrow. Reduced splenic HSC retention may attenuate LPS-induced myelopoiesis. To test this hypothesis, we enumerated myeloid cells and monocytes in the blood (Fig. 6 E) and spleen (Fig. 6 F) and found that VCAM-1 knockdown significantly reduced myeloid cell and monocyte numbers. Collectively, these data demonstrate a requirement for VCAM-1 expression by splenic macrophages for maintaining the organ’s hematopoietic niche. VLA-4 is an integrin expressed by leukocytes that binds with VCAM-1 on activated endothelial cells (Elices et al., 1990), resulting in recruitment of inflammatory cells to sites of inflammation. Similarly, VCAM-1 expressed by splenic macrophages may bind with VLA-4 expressed by HSCs (Williams et al., 1991). To investigate an interaction of VCAM-1 with VLA-4 in this setting, we transferred GFP+ HSPCs into LPS-treated mice after VLA-4 neutralization with an antibody. We found that this blocking antibody significantly decreased splenic HSPC retention (Fig. 6 G).
Affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114 email@example.com firstname.lastname@example.org.