title: 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.
abstract: BACKGROUND
  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, 3×10(6) 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.
authors.affiliation: EIT/LOFUS R&D Center, International St. Mary's Hospital, Simgokro 100beongil 25, Incheon, 404-834, Republic of Korea. songbw@ish.or.kr.
authors.forename: Byeong-Wook
authors.initials: BW
authors.lastname: Song
authors.affiliation: Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University Gangneung, Beomilro 579beongil 24, Gangwon-do, 210-701, Republic of Korea. ilkwonkim@ish.or.kr.
authors.forename: Il-Kwon
authors.initials: IK
authors.lastname: Kim
authors.affiliation: Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University Gangneung, Beomilro 579beongil 24, Gangwon-do, 210-701, Republic of Korea. sam1017@ish.or.kr.
authors.forename: Seahyoung
authors.initials: S
authors.lastname: Lee
authors.affiliation: Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University Gangneung, Beomilro 579beongil 24, Gangwon-do, 210-701, Republic of Korea. ehchoi@ish.or.kr.
authors.forename: Eunhyun
authors.initials: E
authors.lastname: Choi
authors.affiliation: Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Yeonsero 50, Seoul, 120-752, Republic of Korea. ojham@yuhs.ac.
authors.forename: Onju
authors.initials: O
authors.lastname: Ham
authors.affiliation: Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Yeonsero 50, Seoul, 120-752, Republic of Korea. sylee31@yuhs.ac.
authors.forename: Se-Yeon
authors.initials: SY
authors.lastname: Lee
authors.affiliation: Department of Integrated Omics for Biomedical Sciences, Yonsei University, Yeonsero 50, Seoul, 120-752, Republic of Korea. cylee083@gmail.com.
authors.forename: Chang Yeon
authors.initials: CY
authors.lastname: Lee
authors.affiliation: Department of Integrated Omics for Biomedical Sciences, Yonsei University, Yeonsero 50, Seoul, 120-752, Republic of Korea. yrjgmb@yuhs.ac.
authors.forename: Jun-Hee
authors.initials: JH
authors.lastname: Park
authors.affiliation: Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Yeonsero 50, Seoul, 120-752, Republic of Korea. jylee12@yuhs.ac.
authors.forename: Jiyun
authors.initials: J
authors.lastname: Lee
authors.affiliation: Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Yeonsero 50, Seoul, 120-752, Republic of Korea. shh17@yuhs.ac.
authors.forename: Hyang-Hee
authors.initials: HH
authors.lastname: Seo
authors.affiliation: Department of Biology Education, Pusan National University, Busandaehakro 63beongil 2, Busan, 609-735, Republic of Korea. cwc1975@hanmail.net.
authors.forename: Woochul
authors.initials: W
authors.lastname: Chang
authors.affiliation: Department of Cardiovascular & Thoracic Surgery, College of Medicine, Catholic Kwandong University, Beomilro 579beongil 24, Gangneung, Gangwon-do, 210-701, Republic of Korea. csyoon@ish.or.kr.
authors.forename: Cheesoon
authors.initials: C
authors.lastname: Yoon
authors.affiliation: Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University Gangneung, Beomilro 579beongil 24, Gangwon-do, 210-701, Republic of Korea. kchwang@cku.ac.kr.
authors.forename: Ki-Chul
authors.initials: KC
authors.lastname: Hwang
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology; D007211:Indoles / Q000494:pharmacology*; D008301:Maleimides / Q000494:pharmacology*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018800:Thy-1 Antigens / Q000235:genetics / Q000378:metabolism; D057772:Vascular System Injuries / Q000628:therapy*; D014945:Wound Healing
chemical_list: D007211:Indoles; D008301:Maleimides; D019408:Platelet Endothelial Cell Adhesion Molecule-1; C417521:SB 216763; D018800:Thy-1 Antigens