title: The sulfated polysaccharide fucoidan rescues senescence of endothelial colony-forming cells for ischemic repair.
abstract: The efficacy of cell therapy using endothelial colony-forming cells (ECFCs) in the treatment of ischemia is limited by the replicative senescence of isolated ECFCs in vitro. Such senescence must therefore be overcome in order for such cell therapies to be clinically applicable. This study aimed to investigate the potential of sulfated polysaccharide fucoidan to rescue ECFCs from cellular senescence and to improve in vivo vascular repair by ECFCs. Fucoidan-preconditioning of senescent ECFCs was shown by flow cytometry to restore the expression of functional ECFC surface markers (CD34, c-Kit, VEGFR2, and CXCR4) and stimulate the in vitro tube formation capacity of ECFCs. Fucoidan also promoted the expression of cell cycle-associated proteins (cyclin E, Cdk2, cyclin D1, and Cdk4) in senescent ECFCs, significantly reversed cellular senescence, and increased the proliferation of ECFCs via the FAK, Akt, and ERK signaling pathways. Fucoidan was found to enhance the survival, proliferation, incorporation, and endothelial differentiation of senescent ECFCs transplanted in ischemic tissues in a murine hind limb ischemia model. Moreover, ECFC-induced functional recovery and limb salvage were markedly improved by fucoidan pretreatment of ECFCs. To our knowledge, the findings of our study are the first to demonstrate that fucoidan enhances the neovasculogenic potential of ECFCs by rescuing them from replicative cellular senescence. Pretreatment of ECFCs with fucoidan may thus provide a novel strategy for the application of senescent stem cells to therapeutic neovascularization.
authors.affiliation: Laboratory for Vascular Medicine and Stem Cell Biology, Department of Physiology, Medical Research Institute, School of Medicine, Pusan National University, Yangsan, Korea.
authors.forename: Jun Hee
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Soonchunhyang Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Yongsan-gu, Seoul, Korea.|Department of Biochemistry, School of Medicine, Soonchunhyang University, Cheonan, Korea.
authors.forename: Sang Hun
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Laboratory for Vascular Medicine and Stem Cell Biology, Department of Physiology, Medical Research Institute, School of Medicine, Pusan National University, Yangsan, Korea.
authors.forename: Sung Hyun
authors.initials: SH
authors.lastname: Choi
authors.affiliation: Department Regenerative Medicine Science, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Asahara
authors.affiliation: Laboratory for Vascular Medicine and Stem Cell Biology, Department of Physiology, Medical Research Institute, School of Medicine, Pusan National University, Yangsan, Korea.
authors.forename: Sang-Mo
authors.initials: SM
authors.lastname: Kwon
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D064987:Cell- and Tissue-Based Therapy / Q000379:methods; D016922:Cellular Senescence / Q000187:drug effects*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D007511:Ischemia / Q000628:therapy*; D008807:Mice, Inbred BALB C; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011134:Polysaccharides / Q000494:pharmacology*; D033581:Stem Cell Transplantation / Q000379:methods; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects
chemical_list: D011134:Polysaccharides; C007789:fucoidan
keywords: Akt; ERK; Endothelial colony-forming cells; Fucoidan; Replicative cellular senescence; Vascular repair