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J. Wang, K. Ohno-Matsui, T. Yoshida, N. Shimada, M. Mochizuki, I. Morita; Molecular Mechanism of the Enhanced Migration of Endothelial Progenitor Cells Induced by Amyloid β. Invest. Ophthalmol. Vis. Sci. 2010;51(13):4097.
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© ARVO (1962-2015); The Authors (2016-present)
We previously reported that the endothelial progenitor cells (EPCs) contributed to the development of CNV via matrix degrading enzyme; cathepsin L, and that amyloid β (Aβ) enhanced the production of some cytokines in inflammatory cells. In the present study, we focused on Aβ, which is accumulated within drusen of age-related macular degeneration (AMD), and investigated the molecular mechanism of the recruitment of EPCs to subretinal space secondary to Aβ accumulation.
Human umbilical cords and cord bloods were obtained from healthy newborns. HUVEC were isolated from umbilical cord veins and EPCs were isolated from the cultivation of mononuclear cells in human cord blood. Human primary RPE cells as well as EPCs were stimulated by Aβ or pro-inflammatory cytokines (IL-1β, TNF-α, IFN-γ) . The mRNA expression of fractalkine and its receptor; CX3CR1 was analyzed by real-time PCR. Migratory activity of EPCs was measured by Boyden chamber assay.
EPCs expressed significantly higher levels of CX3CR1 compared to mature vascular endothelial cells like HUVEC without any stimuli. Aβ treatment induced a significant increase of CX3CR1 expression in EPCs. In RPE cells, the expression of fractalkine was not changed by Aβ stimulation, however, the treatment with IL-1β, TNF-α, or IFN-γ significantly increased the expression of fractalkine. In Boyden chamber assay, fractalkine caused a remarkable migration of EPCs in a dose-dependent manner. Finally, fractalkine-induced migration of EPCs was significantly enhanced in Aβ-treated EPCs compared to non-treated EPCs.
These results suggest the possibility that Aβ causes the migration of EPCs to the area of drusen via up-regulation of CX3CR1 in EPCs as well as cytokine-induced up-regulation of fractalkine in RPE. This phenomenon might be an important process for the CNV development in AMD.
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