AORTIC MSCS MEDIATE THE ATHEROSCLEROTIC DISEASE DEVELOPMENT THROUGH INCREASED EXPRESSION OF MMP-9 AND ENHANCED OSTEOGENIC DIFFERENTIATION

Aim: Aortic MSCs may participate at the human atherosclerotic disease development; a defected or abnormal differentiation process can determine exaggerate calcium deposition and matrix remodeling. Our aim was to isolate MSCs from human atherosclerotic aneurysm and to explore their potential contribution to the disease progression. Methods:This study included aneurysm sac of ten patients after surgical repair and cryopreserved healthy aortic tissues. MSCs were obtained through enzymatic digestion and characterized by flow cytometer; ha-MSCs and AAA-MSCs were compared for multilineage potential, immunomodulation and MMP expression. Then, ha-MSCs were exposed to a cytokine cocktail (TNF-alpha/IL-1 beta) for 24 h, to test the inflammatory influence on differentiation and vascular remodeling. Results: Both healthy and AAA MSCs possessed fibroblast morphology and expressed CD90, CD73, CD105 and CD44 markers. AAA-MSCs underwent osteogenic differentiation more efficiently than healthy, according to the intensive calcium staining which correlated with higher BMP-2 and OPN transcription. Increased mRNA of osteogenic markers and mineralization process also occurred when ha-MSCs were treated with inflammatory cytokines. Compared to healthy, AAA MSCs also displayed high mRNA and protein levels of MMP-9, as well as a pronounced enzymatic activity, thus suggesting an enhanced remodeling activity. Conversely to ha-MSCs, AAA-MSCs had a reduced immunomodulation potential. Conclusions: MSC differentiation critically contributes to the progression of atherosclerotic diseases and it is tightly associated with inflammation. In this regard, the inefficient MSC immunomodulation exacerbates the inflammatory process. The development of molecular strategies aimed at control and/or reverse MSC defects could represent a novel approach for arterial calcification regression.