Bone Marrow-Derived Mesenchymal Stem Cells Ameliorate Hepatic Ischemia Reperfusion Injury in a Rat Model Hiroyuki Kanazawa1,2*, Yasuhiro Fujimoto1, Takumi Teratani1, Junji Iwasaki1,2, Naoya Kasahara1, Kouji Negishi1, Tatsuaki Tsuruyama 2 , Shinji Uemoto3, Eiji Kobayashi1 1 Division of Development of Advanced Treatment, Center for Development of Advanced Medical Technology, Jichi Medical University, Yakushiji City, Tochigi, Japan, 2 Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto City, Kyoto, Japan, 3 Department of Hepato-pancreato-biliary Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto City, Kyoto, Japan Abstract Background: Ischemia-reperfusion (I/R) injury associated with living donor liver transplantation impairs liver graft regeneration. Mesenchymal stem cells (MSCs) are potential cell therapeutic targets for liver disease. In this study, we demonstrate the impact of MSCs against hepatic I/R injury and hepatectomy. Methodology/Principal Findings: We used a new rat model in which major hepatectomy with I/R injury was performed. Male Lewis rats were separated into two groups: an MSC group given MSCs after reperfusion as treatment, and a Control group given phosphate-buffered saline after reperfusion as placebo. The results of liver function tests, pathologic changes in the liver, and the remnant liver regeneration rate were assessed. The fate of transplanted MSCs in the luciferase- expressing rats was examined by in vivo luminescent imaging. The MSC group showed peak luciferase activity of transplanted MSCs in the remnant liver 24 h after reperfusion, after which luciferase activity gradually declined. The elevation of serum alanine transaminase levels was significantly reduced by MSC injection. Histopathological findings showed that vacuolar change was lower in the MSC group compared to the Control group. In addition, a significantly lower percentage of TUNEL-positive cells was observed in the MSC group compared with the controls. Remnant liver regeneration rate was accelerated in the MSC group. Conclusions/Significance: These data suggest that MSC transplantation provides trophic support to the I/R-injured liver by inhibiting hepatocellular apoptosis and by stimulating regeneration. Citation: Kanazawa H, Fujimoto Y, Teratani T, Iwasaki J, Kasahara N, et al. (2011) Bone Marrow-Derived Mesenchymal Stem Cells Ameliorate Hepatic Ischemia Reperfusion Injury in a Rat Model. PLoS ONE 6(4): e19195. doi:10.1371/journal.pone.0019195 Editor: Carlo Gaetano, Istituto Dermopatico dell’Immacolata, Italy Received December 13, 2010; Accepted March 22, 2011; Published April 29, 2011 Copyright: 2011 Kanazawa et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The authors have no support or funding to report. Competing Interests: Author Eiji Kobayashi is a special advisor to Otsuka Pharmaceutical Co., Ltd. There are no patents, products in development or marketed products to declare. This does not alter the authors’ adherence to all the PLoS ONE policies on sharing data and materials, as detailed online in the guide for authors. The other authors declare no competing financial interests. * E-mail: kagoshimakurobuta@hotmail.com Introduction Liver transplantation is one of the most efficient treatments available for various end-stage hepatic diseases. However, one of the major limitations of liver transplantation is the scarcity of donor organs. To overcome this limitation, split liver transplan- tation or living donor liver transplantation are performed and show the most promising outcomes. However, when these treatments are performed in adult recipients with adult living donors, size mismatch between graft and recipient becomes a critical problem. The first priority is donor safety, and so smaller sized grafts such as the left-lobe of the liver seem to be the optimal choice [1]. Liver transplantation does inevitably lead to hepatic ischemia- reperfusion (I/R) injury. Primary graft non-function or dysfunc- tion, which occurs as a result of combined I/R injury and secondary tissue regeneration impairment, remains a serious complication in the clinical practice, and this is especially the case for transplantation of livers that are small-for-size [2,3]. Therefore, many studies have tried to elucidate the mechanisms of I/R injury by means of appropriate in vivo models. Effective treatment strategies aimed at reducing hepatic I/R injury and accelerating liver regeneration could offer major benefits in liver transplantations involving size mismatch of graft and recipient. Recent reports have demonstrated the capacity of mesenchymal stem cells (MSCs) to specifically be involved in the repair of organ tissue. These results indicate that MSCs are an attractive cell source for regenerative medicine. As for the liver, most animal studies have been carried out in drug-induced rodent models [4,5,6]. However, the role of MSCs in hepatic I/R injury remains to be established. Here, we show that transplanted MSCs are able to ameliorate hepatic I/R injury and significantly improve liver regeneration. PLoS ONE | www.plosone.org 1 April 2011 | Volume 6 | Issue 4 | e19195