Accelerated reendothelialization by intravenous endothelial-like cells differentiated from mesenchymal stem cells

Abstract

[한글]

[영문]Recent studies have suggested that endothelial progenitor cells (EPCs) can accelerate reendothelialization, but difficulty in obtaining sufficient numbers of cells has limited the therapeutic use of blood-derived EPCs. Primitive and undifferentiated bone marrow cells contribute to the formation of the neointimal region. In a previous study, we screened 41 inhibitors of six major protein kinase subfamilies to determine if any of these inhibitors altered the orchestration of multiple signaling pathways involved in stem cell differentiation. Glycogen synthase kinase-3β(GSK-3β) inhibitors promoted the differentiation of mesenchymal stem cells into endothelial-like cells, and endothelial-specific markers (CD31, eNOS, VE-cadherin, VCAM-1, VEGF-R2, vWF) were upregulated in these endothelial-like cells (G-MSCs). In addition, endothelial-like cells differentiated from MSCs accelerated reendothelialization in a balloon-injured (BI) rat model. GFP-labeled G-MSCs or MSCs were injected into BI rats intravenously(3x106 cells/animal). Five days after injection, the denuded area was markedly reduced in BI rats injected with G-MSCs compared to rats received MSCs. Furthermore, less neointimal hyperplasia formation following vascular endothelium injury was observed in rats injected with endothelial-like cells compared to rats injected with MSCs. In vivo functional assay of the endothelium dependent vascular relaxation test was performed and the group injected with G-MSCs showed ~20% functional elevation compared with MSCs. Based on results, the injection of endothelial-like cells differentiated from MSCs by GSK-3β inhibition accelerates reendothelialization in BI rat model compared to naive MSCs. This system can potentially be applied to the development of new regenerative medicines for reendothelialization.