Abstract 12921: Hematopoietic Stem/progenitor Cells Contribute to Atherosclerotic Progression Via Integrin aMβ2
Objectives: Inflammatory cells in atherosclerotic plaque are exclusively derived from hematopoietic stem/progenitor cells (HSPC) in bone marrow (BM). Recently, we and others reported HSPC proliferation and differentiation in hypercholesterolemic mice, resulting in increased production of inflammatory cells in the blood. Despite the link between HSPC activation, leukocytosis and accelerated atherosclerosis, there is no direct evidence demonstrating the presence of HSPC in plaques. Moreover, how LDL modulates HSPC in plaque development is not yet defined.
Methods: Eight - twelve week old LDLr-/- mice were fed on chow or high fat diet (1% cholesterol, 34% fat) for 8 weeks. The frequency of HSPC and integrin αMβ2 + HSPC in blood and BM was quantified by FACS. Migration and adhesion of HSPC was assessed in the presence of ICAM-1 ex vivo. In vitro, using pERK inhibitor U0126, the mechanisms underlying the effect of LDL on integrin αMβ2 expression on HSPC was explored. ERK1/2 activation (pERK) in HSPC of LDLr-/- mice was studied by FACS. By immunohistochemistry, the number of CD150+ Sca-1+ HSPC was studied to assess the correlation between HSPC per section and plaque size.
Results: We identified a positive correlation between the number of CD150+Sca-1+ HSPC in plaques and lesion size (n=13, r=0.81, p ≤ 0.001). FACS analysis indicated an increased percentage of integrin αMβ2+ HSPC in blood and BM, which was accompanied with enhanced HSPC adhesion to ICAM-1-coated plate and migration toward ICAM-1. Hypercholesterolemia promoted pERK in HSPC in vivo. In vitro, LDL stimulated integrin αMβ2 + expression in HSPC partially via enhanced trafficking to membrane transportation. Presentation of integrin αMβ2 to membrane was regulated by pERK-dependent ARF1 and pERK-independent LRP1. VLDL and LDL induced HSPC differentiation toward F4/80+ macrophages.
Conclusions: We demonstrated a possible direct role of HSPC in plaque progression, which may be mediated via integrin αMβ2 expression.
- © 2013 by American Heart Association, Inc.