Transfer of Endothelial Progenitor and Bone Marrow Cells Influences Atherosclerotic Plaque Size and Composition in Apolipoprotein E Knockout Mice

Abstract

Objectives-Recent clinical trials use cell therapy with bone marrow (BM) cells or endothelial progenitor cells (EPCs) for ischemic syndromes. We explored the effect of BM cell-or spleen cell-derived EPC transfer on plaque size and stability markers in the apolipoprotein E knockout (apoE KO) mouse model. Methods and Results-ApoE KO mice aged 10 weeks served as recipients. Labeled BM cells and spleen cell-derivedEPCs from age-matched apoE KO mice were injected intravenously to 2 groups of recipient mice each. Additional mice served as controls receiving saline. Both protocols were repeated 3 times at 2 weekly intervals. On killing, plaque size and character were studied, lipid profile analyzed, and serum and aortic cytokines assayed. Spleen cell-derived cells contained a significantly larger number of endothelial cell precursors. Labeled EPCs and BM cells were found abundantly in the spleens, yet also in the lesions of the recipient mice. Aortic sinus lesion size was significantly increased in mice receiving BM cells (nϭ10) in the EPC-treated group (nϭ10) compared with controls (nϭ10; a 54% and a 34% increase in aortic sinus plaque area, respectively). Mice receiving EPCs exhibited plaques with larger lipid cores and thinner fibrous caps and a higher number of infiltrating CD3 cells. RT-PCR analysis of aortas revealed reduced expression of mRNA for interleukin-10 (IL-10) in both cell transfer groups. Higher serum concentrations of IL-6 and monocyte chemoattractant protein-1 were found in sera from BM recipients, whereas lower IL-10 levels were found in mice transfused with spleen-derived EPCs. 1 It is probable that factors that govern the initiation of atherosclerosis, which involves less complex cellular crosstalk, are not identical to determinants of plaque progression, in which additional matrix components and cell types are prevalent. 2 In both these processes, ECs have been proposed to play a major role forming the attachment surface on which monocytes role and adhere. ECs participate in the early fatty streak formation and in constituting the vasa vasorum network that acts to supply the inner growing neointima in more advanced lesions. These actions are regulated by expression of a set of adhesion molecules on the EC surface and by synthesis and secretion of regulatory humoral factors. 1,2 Apparently, confounding data have been provided with regard to the effect of EC on plaque progression and phenotype. Atherosclerosis is a disorder with endothelial dysfunction, and it is thus conceivable that replenishment of ECs would result in attenuated EC activation with consequent inflammation. These findings are supported by a study by Rauscher et al 3 showing that transfer of bone marrow (BM) cells from young apolipoprotein E knockout (apoE KO) mice reduces atherosclerotic plaque size. However, it appears that the angiogenesis inhibitor TNP-470 and angiostatin acting to inhibit plaque neovascularization were found to suppress atherosclerotic lesion development, 4,5 whereas vascular endothelial growth factor promote...

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Endothelial progenitor cells as factors in neovascularization and endothelial repair

“…The systemic application of healthy wild-type EPCs in atherosclerotic apolipoprotein E-knockout mice has been shown to improve endothelial function and to inhibit atherosclerotic lesion progression independent of high serum cholesterol levels [48] . However, these beneficial effects were not observed in a study conducted by George et al [49] in which aortic sinus lesion size was significantly increased in mice receiving EPCs compared with controls. Mice receiving EPCs showed plaques with larger lipid cores, thinner fibrous caps, and a higher number of infiltrating CD3 cells, suggesting an effect on plaque stability.…”