title: Tauroursodeoxycholic acid reduces ER stress by regulating of Akt-dependent cellular prion protein.
abstract: Although mesenchymal stem cells (MSCs) are a promising cell source for regenerative medicine, ischemia-induced endoplasmic reticulum (ER) stress induces low MSC engraftment and limits their therapeutic efficacy. To overcome this, we investigated the protective effect of tauroursodeoxycholic acid (TUDCA), a bile acid, on ER stress in MSCs in vitro and in vivo. In ER stress conditions, TUDCA treatment of MSCs reduced the activation of ER stress-associated proteins, including GRP78, PERK, eIF2α, ATF4, IRE1α, JNK, p38, and CHOP. In particular, TUDCA inhibited the dissociation between GRP78 and PERK, resulting in reduced ER stress-mediated cell death. Next, to explore the ER stress protective mechanism induced by TUDCA treatment, TUDCA-mediated cellular prion protein (PrPC) activation was assessed. TUDCA treatment increased PrPCexpression, which was regulated by Akt phosphorylation. Manganese-dependent superoxide dismutase (MnSOD) expression also increased significantly in response to signaling through the TUDCA-Akt axis. In a murine hindlimb ischemia model, TUDCA-treated MSC transplantation augmented the blood perfusion ratio, vessel formation, and transplanted cell survival more than untreated MSC transplantation did. Augmented functional recovery following MSC transplantation was blocked by PrPCdownregulation. This study is the first to demonstrate that TUDCA protects MSCs against ER stress via Akt-dependent PrPCand Akt-MnSOD pathway.
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 Pharmacology and Toxicology, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35294, USA.
authors.forename: Jun Hee
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, USA.
authors.forename: Seung Pil
authors.initials: SP
authors.lastname: Yun
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: Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul, Republic of Korea.
authors.forename: Chul Won
authors.initials: CW
authors.lastname: Yun
authors.affiliation: Department of Veterinary Physiology, College of Veterinary Medicine and Research Institute for Veterinary Science, and BK21 PLUS Creative Veterinary Research Center, Seoul National University, Seoul 151-741, Republic of Korea.
authors.forename: Hyun Jik
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Hyonam Kidney Laboratory, Soonchunhyang University, Seoul, Republic of Korea.
authors.forename: Hyunjin
authors.initials: H
authors.lastname: Noh
authors.affiliation: Department of Veterinary Physiology, College of Veterinary Medicine and Research Institute for Veterinary Science, and BK21 PLUS Creative Veterinary Research Center, Seoul National University, Seoul 151-741, Republic of Korea.
authors.forename: Sei-Jung
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Department of Veterinary Physiology, College of Veterinary Medicine and Research Institute for Veterinary Science, and BK21 PLUS Creative Veterinary Research Center, Seoul National University, Seoul 151-741, Republic of Korea.
authors.forename: Ho Jae
authors.initials: HJ
authors.lastname: Han
authors.affiliation: Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul, Republic of Korea.|Departments of Biochemistry, Soonchunhyang University College of Medicine, Cheonan, 330-930, Republic of Korea.
authors.forename: Sang Hun
authors.initials: SH
authors.lastname: Lee
mesh_terms: D000818:Animals; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D064593:Heterografts; D006801:Humans; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018621:PrPC Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology*
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D018621:PrPC Proteins; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; D051057:Proto-Oncogene Proteins c-akt