title: Fucoidan protects mesenchymal stem cells against oxidative stress and enhances vascular regeneration in a murine hindlimb ischemia model.
abstract: BACKGROUND
  Mesenchymal stem cells (MSCs) have the potential to differentiate into multiple cell lineages. Given this potential for tissue regeneration, MSC-based therapeutic applications have been considered in recent years. However, ischemia-induced apoptosis has been reported to be one of the main causes of MSC death following transplantation. The primary objective of this study was to determine whether a natural antioxidant, fucoidan, could protect MSCs from ischemia-induced apoptosis in vitro and in vivo. Furthermore, we investigated the mechanism of action of fucoidan's anti-ischemic effect in MSCs.
  
  
  RESULTS
  Pre-treatment with fucoidan (10 μg/mL) suppressed the increase in H2O2-induced reactive oxygen species (ROS) levels and drastically reduced apoptotic cell death in MSCs. Fucoidan inhibited the activation of the pro-apoptotic proteins p38-mitogen-activated protein kinase (MAPK), Jun N-terminal kinase (JNK), and caspase-3, and augmented the expression of the anti-apoptosis protein cellular inhibitor of apoptosis (cIAP). Moreover, fucoidan significantly increased manganese superoxide dismutase (MnSOD) expression and decreased cellular ROS levels via the Akt pathway, resulting in enhanced cell survival. In a murine hindlimb ischemia model, transplanted fucoidan-treated MSCs showed significantly enhanced cell survival and proliferation in ischemic tissues. Functional recovery and limb salvage also remarkably improved in mice injected with fucoidan-stimulated MSCs compared with mice injected with non-stimulated MSCs.
  
  
  CONCLUSIONS
  Taken together, these results show that fucoidan protects MSCs from ischemia-induced cell death by modulation of apoptosis-associated proteins and cellular ROS levels through regulation of the MnSOD and Akt pathways, suggesting that fucoidan could be powerful therapeutic adjuvant for MSC-based therapy in ischemic diseases.
authors.affiliation: Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul, Republic of Korea.
authors.forename: Yong-Seok
authors.initials: YS
authors.lastname: Han
authors.affiliation: Laboratory for Vascular Medicine and Stem Cell Biology, Medical Research Institute, Department of Physiology, School of Medicine, Pusan National University, Yangsan 626-870, Republic of Korea.
authors.forename: Jun Hee
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Medical Research Center for Ischemic Tissue Engineering, Pusan National University, Yangsan, Gyeongnam, Republic of Korea; Department of Physiology, School of Medicine, Pusan National University, Yangsan, Gyeongnam, Republic of Korea.
authors.forename: Jin Sup
authors.initials: JS
authors.lastname: Jung
authors.affiliation: Department of Internal Medicine, Soonchunhyang University, Seoul, Republic of Korea; Hyonam Kidney Laboratory, Soonchunhyang University, Seoul, Republic of Korea.
authors.forename: Hyunjin
authors.initials: H
authors.lastname: Noh
authors.affiliation: Department of Surgery, School of Medicine, Soonchunhyang University, Cheonan 330-930, Republic of Korea.
authors.forename: Moo Jun
authors.initials: MJ
authors.lastname: Baek
authors.affiliation: Department of Veterinary Physiology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 151-741, Republic of Korea; BK21 PLUS Creative Veterinary Research Center, Seoul National University, Seoul 151-741, Republic of Korea.
authors.forename: Jung Min
authors.initials: JM
authors.lastname: Ryu
authors.affiliation: Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul, Republic of Korea.
authors.forename: Yeo Min
authors.initials: YM
authors.lastname: Yoon
authors.affiliation: Department of Veterinary Physiology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 151-741, Republic of Korea; BK21 PLUS Creative Veterinary Research Center, Seoul National University, Seoul 151-741, Republic of Korea. Electronic address: hjhan@snu.ac.kr.
authors.forename: Ho Jae
authors.initials: HJ
authors.lastname: Han
authors.affiliation: Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul, Republic of Korea; Department of Biochemistry, Soonchunhyang University College of Medicine, Cheonan 330-930, Republic of Korea. Electronic address: ykckss1114@nate.com.
authors.forename: Sang Hun
authors.initials: SH
authors.lastname: Lee
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D006614:Hindlimb / Q000098:blood supply*; D006801:Humans; D007511:Ischemia / Q000188:drug therapy* / Q000473:pathology; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D011134:Polysaccharides / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D011134:Polysaccharides; C007789:fucoidan
keywords: Fucoidan; MSCs; MnSOD; Survival; Vascular repair