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 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.
Highlights
Mesenchymal stem cells (MSCs) are promising candidates for cell-based therapies in regenerative medicine owing to their self-renewal, multidirectional differentiation, and immunomodulation potential[1]
To investigate reactive oxidative species (ROS)-mediated ER stress in ischemic conditions in vivo, the expression and activation of ER stress-associated proteins (78-kDa glucose-regulated protein (GRP78), protein kinase R-like endoplasmic reticulum kinase (PERK), eukaryotic initiation factor 2-alpha, activating transcription factor 4 (ATF4), inositol-requiring protein 1 alpha (IRE1α), c-Jun N-terminal kinase (JNK), p38, and CCAAT-enhancer-binding protein homologous protein (CHOP)) in normal and ischemic-injured tissues were determined by western blot analysis (Fig. 1c–f)
Our findings indicate that ischemic injury induces ROS generation, and that GRP78, PERK, eIF2α, and ATF4 are subsequently activated, resulting in the induction of ER stress mediated-apoptosis cascades
Summary
Mesenchymal stem cells (MSCs) are promising candidates for cell-based therapies in regenerative medicine owing to their self-renewal, multidirectional differentiation, and immunomodulation potential[1]. Application of MSCs in cell therapy has shown low therapeutic efficacy resulting from various stress conditions, including oxidative stress, inflammation, and toxic environments cause by ischemia[1,2]. Under these pathophysiological conditions, oxidative stress induced the production of reactive oxidative species (ROS), resulting in prolonged endoplasmic reticulum (ER) stress[3]. Roles PrPC plays in the survival of transplanted stem cells may provide insights into the protection of MSCs and development of PrPC-targeted therapeutics. Results of this study reveal the mechanism by which TUDCA protects against oxidative stress by regulating Akt-dependent PrPC expression
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