1. 1H-pyrrole-2,5-dione-based small molecule-induced generation of mesenchymal stem cell-derived functional endothelial cells that facilitate rapid endothelialization after vascular injury
- Author
-
Ki-Chul Hwang, Il-Kwon Kim, Hyang-Hee Seo, Jiyun Lee, Byeong-Wook Song, Jun-Hee Park, Onju Ham, Cheesoon Yoon, Seahyoung Lee, Chang Yeon Lee, Se-Yeon Lee, Eunhyun Choi, and Woochul Chang
- Subjects
CD31 ,Neointima ,medicine.medical_specialty ,Indoles ,Endothelium ,Medicine (miscellaneous) ,Mesenchymal Stem Cell Transplantation ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Endothelial cell differentiation ,Maleimides ,Rats, Sprague-Dawley ,medicine ,Animals ,Cells, Cultured ,Wound Healing ,business.industry ,Research ,Mesenchymal stem cell ,Endothelial Cells ,Cell Differentiation ,Mesenchymal Stem Cells ,Cell Biology ,Vascular System Injuries ,Surgery ,Cell biology ,Rats ,Endothelial stem cell ,Platelet Endothelial Cell Adhesion Molecule-1 ,medicine.anatomical_structure ,Molecular Medicine ,Thy-1 Antigens ,Endothelium, Vascular ,Stem cell ,business ,Wound healing - Abstract
Introduction 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. 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. Methods Small 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. Results PCA 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. Conclusions Small 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.
- Published
- 2015