The protective effect of bone marrow-derived mesenchymal stem cells in liver ischemia/reperfusion injury via down-regulation of miR-370

Document Type : Original Article


1 Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

2 Department of Pathology, University of Toronto, Toronto, Canada


Objective(s): Liver transplantation is the most important therapy for end-stage liver disease and ischemia reperfusion (I/R) injury is indeed a risk factor for hepatic failure after grafting. The role of miRNAs in I/R is not completely understood. The aim of this study was to investigate the potential protective role of the mesenchymal stem cells (MSCs) and ischemic preconditioning on miR-370 expression and tissue injury in hepatic I/R injury.
Materials and Methods: In this study, 24 BALB/c mice were divided into 4 groups, including sham, I/R, I/R mouse that received MSCs (I/R+MSC) and ischemia preconditioning (IPC) The expression levels of hepatic miR-370, Bcl2 and BAX in male BALB/c mice in different groups including hepatic I/R, hepatic I/R received MSCs, and hepatic I/R with IPC were assessed by quantitative real-time PCR. The effect of miR-370 on hepatic I/R was investigated by serum liver enzyme analysis and histological examination.
Results: The expression of miR-370 was significantly up-regulated in the mice subjected to hepatic I/R injury as compared with the sham operated mice. Injection of MSCs led to the down-regulation of the serum liver enzymes, expression of miR-370 and BAX, up-regulation of Bcl2 as well as the improvement of hepatic histological damage. IPC led to similar results, but the difference was not significant.
Conclusion: Our data suggest that miR-370 affected the Blc2/BAX pathway in hepatic I/R injury, and down- regulation of miR-370 by BM-MSCs efficiently attenuated the liver damage.


Main Subjects

1. Peralta C, Jiménez-Castro MB, Gracia-Sancho J. Hepatic ischemia and reperfusion injury: effects on the liver sinusoidal milieu. J Hepatol 2013; 59:1094-1106.
2. Montalvo-Jave EE, Piña E, Montalvo-Arenas C, Urrutia R, Benavente-Chenhalls L, Peña-Sanchez J, et al. Role of ischemic preconditioning in liver surgery and hepatic transplantation. J Gastrointes Surg 2009; 13:2074-2083.
3. Palanisamy AP, Cheng G, Sutter AG, Liu J, Lewin DN, Chao J, et al. Adenovirus-mediated eNOS expression augments liver injury after ischemia/reperfusion in mice. PloS One 2014; 9:e93304-e93312.
4. Eltzschig HK, Eckle T. Ischemia and reperfusion [mdash] from mechanism to translation. Nat Med 2011; 17:1391-1401.
5. Abu‐Amara M, Yang SY, Tapuria N, Fuller B, Davidson B, Seifalian A. Liver ischemia/reperfusion injury: processes in inflammatory networks—a review. Liver Transpl 2010; 16:1016-1032.
6. Madrigal M, Rao KS, Riordan NH. A review of therapeutic effects of mesenchymal stem cell secretions and induction of secretory modification by different culture methods. J Transl Med 2014; 12:260-273.
7. Rowart P, Erpicum P, Detry O, Weekers L, Grégoire C, Lechanteur C, et al. Mesenchymal stromal cell therapy in ischemia/reperfusion injury. J Immunol Res 2015;2015:602597.
8. Du T, Ju G, Wu S, Cheng Z, Cheng J, Zou X, et al. Microvesicles derived from human Wharton’s jelly mesenchymal stem cells promote human renal cancer cell growth and aggressiveness through induction of hepatocyte growth factor. PloS One 2014; 9:e96836-e96846.
9. Shen B, Liu J, Zhang F, Wang Y, Qin Y, Zhou Z, et al. CCR2 positive exosome released by mesenchymal stem cells suppresses macrophage functions and alleviates ischemia/reperfusion-induced renal injury. Stem Cells Int 2016; 2016:1240301-1240309.
10. Zou X, Gu D, Xing X, Cheng Z, Gong D, Zhang G, et al. Human mesenchymal stromal cell-derived extracellular vesicles alleviate renal ischemic reperfusion injury and enhance angiogenesis in rats. Am J Transl Res 2016; 8:4289-4299.
11. Pan G-z, Yang Y, Zhang J, Liu W, Wang G-y, Zhang Y-c, et al. Bone marrow mesenchymal stem cells ameliorate hepatic ischemia/reperfusion injuries via inactivation of the MEK/ERK signaling pathway in rats. J Surg Res 2012; 178:935-948.
12. Li L, Li G, Yu C, Shen Z, Xu C, Feng Z, et al. A role of microRNA-370 in hepatic ischaemia-reperfusion injury by targeting transforming growth factor-β receptor II. Liver Int 2015; 35:1124-1132.
13. Abe Y, Hines I, Zibari G, Grisham MB. Hepatocellular protection by nitric oxide or nitrite in ischemia and reperfusion injury. Arc biochem biophys 2009; 484:232-237.
14. Suzuki S, Nakamura S, Koizumi T, Sakaguchi S, Baba S, Muro H, et al. The beneficial effect of a prostaglandin 12 analog on ischemic rat liver. Transplantation 1991; 52:979-983.
15. Chen C-Z, Li L, Lodish HF, Bartel DP. MicroRNAs modulate hematopoietic lineage differentiation. Science 2004; 303:83-86.
16. Esquela-Kerscher A, Slack FJ. Oncomirs—microRNAs with a role in cancer. Nat Rev Cancer 2006; 6:259-269.
17. Fan C, Liu S, Zhao Y, Han Y, Yang L, Tao G, et al. Upregulation of miR-370 contributes to the progression of gastric carcinoma via suppression of FOXO1. Biomed Pharmacother 2013; 67:521-526.
18. Sun G, Hou YB, Jia HY, Bi XH, Yu L, Chen DJ. MiR-370 promotes cell death of liver cancer cells by Akt/FoxO3a signalling pathway. Eur Rev Med Pharmacol Sci 2016; 20:2011-2019.
19. Yungang W, Xiaoyu L, Pang T, Wenming L, Pan X. miR-370 targeted FoxM1 functions as a tumor suppressor in laryngeal squamous cell carcinoma (LSCC). Biomed Pharmacother 2014; 68:149-154.
20. Wu Z, Sun H, Zeng W, He J, Mao X. Upregulation of mircoRNA-370 induces proliferation in human prostate cancer
cells by downregulating the transcription factor FOXO1. PLoS One 2012; 7:e45825-e45835.
21. Iliopoulos D, Drosatos K, Hiyama Y, Goldberg IJ, Zannis VI. MicroRNA-370 controls the expression of microRNA-122 and Cpt1α and affects lipid metabolism. J Lipid Res 2010; 51:1513-1523.
22. Liu H, Yang N, Fei Z, Qiu J, Ma D, Liu X, et al. Analysis of plasma miR-208a and miR-370 expression levels for early diagnosis of coronary artery disease. Biomed Rep 2016; 5:332-336.
23. Ning Y, Li Z, Qiu Z. FOXO1 silence aggravates oxidative stress-promoted apoptosis in cardiomyocytes by reducing autophagy. Journal Toxicol Sciences 2015; 40:637-645.
24. Kayal RA, Siqueira M, Alblowi J, McLean J, Krothapalli N, Faibish D, et al. TNF‐α mediates diabetes‐enhanced chondrocyte apoptosis during fracture healing and stimulates chondrocyte apoptosis Through FOXO1. J Bone Miner Res 2010; 25:1604-1615.
25. Akasaki Y, Alvarez‐Garcia O, Saito M, Caramés B, Iwamoto Y, Lotz MK. FoxO transcription factors support oxidative stress resistance in human chondrocytes. Arthritis Rheumatolo 2014; 66:3349-3358.
26. Shao D, Zhai P, Del Re DP, Sciarretta S, Yabuta N, Nojima H, et al. A functional interaction between Hippo-YAP signalling and FoxO1 mediates the oxidative stress response. Nat Commun 2014; 5:3315-3337.
27. Vascotto C, Cesaratto L, D’Ambrosio C, Scaloni A, Avellini C, Paron I, et al. Proteomic analysis of liver tissues subjected to early ischemia/reperfusion injury during human orthotopic liver transplantation. Proteomics 2006; 6:3455-3465.
28. Kienle K, Rentsch M, Müller T, Engelhard N, Vogel M, Jauch KW, et al., editors. Expression of BCL-2 in liver grafts after adenoviral transfer improves survival following prolonged ischemia and reperfusion in rat liver transplantation. Transplan Proc; 2005; 37:439-441.
29. Park MS, Joo SH, Kim BS, Lee JW, Kim YI, Hong MK, et al. Remote preconditioning on rat hepatic ischemia–reperfusion injury downregulated Bax and cleaved caspase-3 expression. Transplant Proc 2016; 48:1247-1250.
30. Shin JK, Kang JW, Lee SM. Enhanced nitric oxide-mediated
autophagy contributes to the hepatoprotective effects of ischemic preconditioning during ischemia and reperfusion.Nitric Oxide 2016; 58:10-19.
31. Nong K, Wang W, Niu X, Hu B, Ma C, Bai Y, et al. Hepatoprotective effect of exosomes from human-induced pluripotent stem cell–derived mesenchymal stromal cells against hepatic ischemia-reperfusion injury in rats. Cytotherapy 2016; 18:1548-1559.