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Sci Rep. 2016 Dec 22;6:39838. doi: 10.1038/srep39838.

Tauroursodeoxycholic acid reduces ER stress by regulating of Akt-dependent cellular prion protein.

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Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul, Republic of Korea.
Department of Pharmacology and Toxicology, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35294, USA.
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, USA.
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.
Department of Internal Medicine, Hyonam Kidney Laboratory, Soonchunhyang University, Seoul, Republic of Korea.
Departments of Biochemistry, Soonchunhyang University College of Medicine, Cheonan, 330-930, Republic of Korea.


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 PrPC expression, 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 PrPC downregulation. This study is the first to demonstrate that TUDCA protects MSCs against ER stress via Akt-dependent PrPC and Akt-MnSOD pathway.

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