Abstract
IntroductionDespite the success of interventional processes such as drug-eluting stents, complete prevention of restenosis is still hindered by impaired or delayed endothelialization or both. Here, we report that 1H-pyrrole-2,5-dione-based small molecule-generated mesenchymal stem cell-derived functional endothelial cells (MDFECs) facilitated rapid transmural coverage of injured blood vessels.MethodsSmall molecules that induced CD31 expression were screened by principal component analysis (PCA). Rat mesenchymal stem cells (MSCs) were treated with selected small molecules for up to 16 days, and the expression levels of CD90 and CD31 were examined by immunocytochemistry. In vitro functional assays of MDFECs, including tube formation assays and nitric oxide production assays, were performed. After MDFECs (intravenous, 3×106 cells per animal) were injected into balloon-injured rats, neointima formation was monitored for up to 21 days. The endothelial coverage of denuded blood vessels was evaluated by Evans Blue staining. The functionality of repaired blood vessels was evaluated by measuring vasorelaxation and hemodynamic changes. Additionally, derivatives of the selected small molecules were examined for their ability to induce endothelial markers.ResultsPCA indicated that 3-(2,4-dichlorophenyl)-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione effectively induced MDFECs. MDFECs inhibited the neointima formation of denuded blood vessels by facilitating more rapid endothelialization. Further examination indicated that derivatives with a 1H-pyrrole-2,5-dione moiety are important for initiating the endothelial cell differentiation of MSCs.ConclusionsSmall molecules with 1H-pyrrole-2,5-dione as a core structure have great potential to improve the efficacy of MSC-based cell therapy for vascular diseases, such as atherosclerosis and restenosis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-015-0170-6) contains supplementary material, which is available to authorized users.
Highlights
Despite the success of interventional processes such as drug-eluting stents, complete prevention of restenosis is still hindered by impaired or delayed endothelialization or both
(See figure on previous page.) Fig. 1 Small molecule-treated Mesenchymal stem cell (MSC) change cell type-specific marker expression and gain angiogenic ability in vitro. a Immunocytochemical monitoring of MSCs treated with SB (1 μM, every 3 days)
Fluorescence intensities are quantified on the upper right side. *P < 0.05. b Endothelial cell (EC) marker gene expression in Induced mesenchymal stem cell-derived functional endothelial cell (iMDFEC). mRNA expression levels of CD34, endothelial nitric oxide synthase (eNOS), VE-cadherin, vascular cell adhesion molecule 1 (VCAM-1), and Vascular endothelial growth factor receptor 1 (Flk-1) were measured by using reverse transcription-polymerase chain reaction
Summary
Despite the success of interventional processes such as drug-eluting stents, complete prevention of restenosis is still hindered by impaired or delayed endothelialization or both. MSCs have been the major type of stem cells for therapy because of their self-renewal and multilineage differentiation ability [7], relatively easy isolation protocol from abundant sources [8,9,10], and low immunogenicity [11, 12]. These characteristics make MSCs the most commonly used stem cells in numerous clinical studies [13]. The concept of changing the fate of stem cells by using small molecules was introduced about a decade ago [18], and our group has empirically demonstrated that it is possible to direct cell fate by using various small molecules [19,20,21]
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