Abstract 1306: Late-outgrowth Endothelial Cells Attenuate Intimal Hyperplasia Contributed By Mesenchymal Stem Cells After Vascular Injury
Objectives: Mesenchymal stem cells (MSCs) from the bone marrow (BM) are pluripotent and have the capacity to differentiate into cardiomyocytes, endothelial cells (ECs), and smooth muscle cells (SMCs). Currently, MSCs are one of a number of cell types undergoing extensive investigation for cardiac regeneration therapy. However, it has not yet been determined whether this cell therapy also substantially contributes to vascular remodeling of diseased vessels, such as in intimal hyperplasia.
Methods and Results: Human MSCs and a variety of progenitor and vascular cells were used for in vitro and in vivo adhesion experiments. To test the contribution of MSCs to intimal hyperplasia, MSCs from eGFP mice were injected via the tail vein of wild-type littermates after femoral artery wire injury. A model of direct BM transplantation of eGFP MSCs into the tibias of irradiated wild-type littermates was also conducted. Wire-induced vascular injury mobilized MSCs into the circulation. Compared to human aortic SMCs, MSCs exhibited a 2.8-fold increase in the adhesion capacity in vitro (p < 0.001), and a 6.3-fold increase in vivo (p < 0.001). In all animal models, immunostaining showed that a significant amount of eGFP MSCs contributed to intimal hyperplasia after vascular injury. Furthermore, MSCs were able to differentiate into cells of endothelial or smooth muscle lineage on the injured vessel wall. Co-culture experiments demonstrated that late-outgrowth ECs guided MSCs to differentiate towards an endothelial lineage through a paracrine effects rather than direct cell-cell interactions. In vivo, cell therapy with late-outgrowth ECs significantly attenuated the thickness of the neointima contributed by MSCs (intima/media ratio, from 3.2 ± 0.4 to 0.4 ± 0.1, p < 0.001).
Conclusions: This study raises concerns about the detrimental effects of stem cell therapy on injured vessel remodeling. Tissue regeneration therapy with MSCs or cell populations containing MSCs requires a strategy to attenuate the high potential of MSCs to develop intimal hyperplasia on diseased vessels.