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ȣ - 540192 4 |
| Intravenous endothelial-like cells differentiated from mesenchymal stem cells contribute to in vivo reendothelialization capacity |
| 연세대학교 의과대학 심혈관 연구소¹, 연세대학교 의과대학 Brain Korea 21 의과학 사업단² , 연세대학교 의과대학 심장내과³ |
| 송병욱¹ ,², 김일권¹ ,² , 최은미¹ , 차민지¹ ,² , 황기철¹, 장양수¹ ,³ |
Background: Recent studies suggested the potential of endothelial progenitor cells (EPCs) for neovascularization and re-endothelization, but the difficulty of obtaining sufficient cells has been an obstacle to the therapeutic use of blood-derived EPCs. Mesenchymal stem cells (MSCs) have the potential to differentiate into various mesenchymal tissues, and great advantages for cell therapy. Primitive and undifferentiated bone marrow cells contribute to the formation of the neointimal region. Method: 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. Moreover, we next examined if the differentiated cells increase the beneficial effects on vascular repair in the balloon-injured rats. Results: Among glycogen synthase kinase-3β (GSK-3β) inhibitors, SB-216763 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. Scanning microscopy (SEM) showed nearly compete reendothelialization of the denuded vessels in the G-MSCs-injected rats. 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. Conclusion: Based on results, the inhibition of GSK-3β leads to the differentiation of MSCs into endothelial-like cells, the injection of these cells accelerates reendothelialization in BI rat model compared to naïve MSCs. This system can potentially be applied to the development of new regenerative medicines for reendothelialization.
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