Macrophage-mimicking adipose-derived stem cells for atherosclerosis targeting and treatment through cell adhesion molecules VCAM-1 and ICAM-1
Background:Atherosclerosis is the major cause of cardiovascular disease. Endothelial injury is one of the initiating factors of atherosclerosis. Injured endothelial cells overexpress adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), facilitating the binding and accumulation of monocytes-macrophages into the vascular wall via the ligands. Adipose-derived stem cells (ADSCs) have been extensively researched for their anti-inflammatory properties and therapeutic potential in various diseases. Targeting atherosclerotic regions with ADSCs may offer a promising therapeutic strategy to alleviate local inflammation associated with atherosclerosis.Methods:The ligands of very late antigen-4 (VLA-4) and lymphocyte function-associated antigen-1 (LFA-1) were expressed in the ADSC to construct the Macrophage (Mf)-mimicking ADSCs. Cell proliferation, adhesion, and migration assays were used to characterize the Mf-mimicking ADSCs. An atherosclerosis model was established in ApoE-/- mice via partial carotid artery ligation. Mf-mimicking ADSCs were administered through tail vein injection. Distribution of these cells was tracked by far-red fluorescent probe. Histological analyses, including H&E staining, Oil Red O staining, and immunofluorescence were conducted to assess the impact on plaque size, composition, and macrophage polarization.Results:Mf-mimicking ADSCs were successfully constructed and characterized. These cells exhibited enhanced adhesion and migration capabilities. The culture medium from Mf-mimicking ADSCs increased the proportion of M2 macrophages and decreased the lipid uptake capacity. In the atherosclerosis mouse model, fluorescently labeled Mf-mimicking ADSCs specifically adhered to and accumulated in atherosclerotic regions, demonstrating targeted localization. Mf-mimicking ADSC treatment resulted in a reduction in plaque size and a decrease in the number of M1 macrophages within the arterial wall.Conclusions:Mf-mimicking ADSCs confirmed their preserved anti-inflammatory properties and enhanced adhesion and migration abilities. In vivo, Mf-mimicking ADSCs exhibited targeted localization ability to regions of endothelial dysfunction in atherosclerosis and attenuate plaque progression. These findings suggest that Mf-mimicking ADSCs may serve as a potential therapeutic strategy for alleviating atherosclerosis and reducing inflammation. Overall design: To investigate the effects of VLA-4 and LFA-1 expression in ADSCs, we analyzed transcriptomic changes in ADSCs overexpressing both VLA-4 and LFA-1 compared to unmodified ADSCs.