Title: Hematopoietic Stem/Progenitor Cells Directly Contribute to Arteriosclerotic Progression Via Integrin Β2
Authors: Wang, Xuhong
Gao, Mingming
Schouteden, Sarah
Roebroek, Anton
Eggermont, Kristel
Van Veldhoven, Paul P
Liu, George
Peters, Thorsten
Scharffetter-Kochanek, Karin
Verfaillie, Catherine #
Feng, Yingmei # ×
Issue Date: Apr-2015
Publisher: AlphaMed Press
Series Title: Stem Cells vol:4 pages:1230-1240
Article number: 10.1002/stem.1939
Abstract: Rationale: Recent studies described the association between hematopoietic stem/progenitor cell (HSPC) expansion in the bone marrow (BM), leukocytosis in the peripheral blood and accelerated atherosclerosis. Objective: We hypothesized that circulating HSPC may home to inflamed vessels, where they might contribute to inflammation and neointima formation. Methods and results: We demonstrated that Lin- Sca-1(+) cKit(+) (LSK cells) in bone marrow (BM) and peripheral blood of LDLr(-/-) mice on high fat diet expressed significantly more integrin β2, which was responsible for LSK cell adhesion and migration toward ICAM-1 in vitro, and homing to injured arteries in vivo, all of which were blocked with an anti-CD18 blocking antibody. When homed LSK cells were isolated from ligated artery and injected to irradiated recipients, they resulted in BM reconstitution. Injection of CD18(+/+) LSK cells to immunodeficient Balb/C Rag2- Ɣ C(-/-) recipients resulted in more severe inflammation and reinforced neointima formation in the ligated carotid artery, compared to mice injected with PBS and CD18(-/-) LSK cells. Hypercholesterolemia stimulated ERK phosphorylation (pERK) in LSK cells of LDLr(-/-) mice in vivo. Blockade of pERK reduced ARF1 expression, leading to decreased integrin β2 function on HSPC. In addition, integrin β2 function could be regulated via ERK-independent LRP1 pathway. Conclusions: Integrin β2 expression on HSPC is regulated by hypercholesterolemia, specifically LDL, in pERK dependent and independent manners, leading to increased homing and localization of HSPC to injured arteries, which is highly correlated with arteriosclerosis. This article is protected by copyright. All rights reserved.
ISSN: 1066-5099
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Lipid Biochemistry and Protein Interactions
Department of Human Genetics - miscellaneous
Stem Cell Biology and Embryology (+)
× corresponding author
# (joint) last author

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