Investigation of the effects of mesenchymal stem cell administration on liver recovery in experimental hepatotoxicity model

Year 2022, , 185 - 193, 31.08.2022

Başak Özgermen , Orhan Yavuz , Ali Evren Haydardedeoğlu

https://doi.org/10.31797/vetbio.1029373

Abstract

Hepatotoxicity refers to liver dysfunction associated with certain medical drugs and chemicals. Studies have shown that mesenchymal stem cells have a positive effect on the improvement of liver diseases. The aim of this study was to investigate the potential protective effects of fetal kidney-induced mesenchymal stem cells on Doxorubicin-induced hepatotoxicity in rats.
Sprague dawley rats were divided into three groups as control, sham, and treatment group. Intraperitoneal mesenchymal stem cells were treated with BrdU prior to transplantation so that they could be followed up after invivo transplantation. After completion of the experimental steps, the groups were monitored for 5 weeks. Then the rats were terminated and their livers were taken for histopathological and immunohistochemical evaluation.
In immunohistochemical examinations performed with TNF-α, Caspase-3 and COX-2 primary antibodies, the most severe positivity was in the sham group, followed by the control and treatment groups. While the control and sham groups were found to be statistically similar in immunohistochemical staining with anti-BrdU antibody, the treatment group was found to be significantly different from the other groups (p<0.05).
As a result, it has been revealed that mesenchymal stem cells administered intraperitoneally to rats with Doxorubicin-induced hepatotoxicity, prevent degeneration and necrosis in hepatocytes, and TNF-α, COX-2, and Caspase-3 levels were significantly decreased immunohistochemically, proving increased liver regeneration.

Keywords

Doxorubicin, Hepatotoxicity, Mesenchimal Stem Cell, Rat

Supporting Institution

Aksaray University Scientific Research Fund

Project Number

2020-029

References

• Alegra, C.J., Curt, G.A., et al. (2006). Chemotherapy of neoplastic diseases. In Brunton, L.L.,Lazo, J.S., Parker, K.L. (Eds.), Goodman&Gilman's the Pharmacological Basis of Therapeutics (pp. 1315–1404). McGraw-Hill, New York.
• Amin, M.A., Sabry, D., Rashed, L.A., et al. (2013). Short-term evaluation of autologous transplantation of bone marrow-derived mesenchymal stem cells in patients with cirrhosis: Egyptian study. Clin Transplant, 27,607-612.
• Cengiz, O., Baran, M., Balcioglu, E., Suna, P.A., Bilgici, P., Goktepe, O., Onder, G.O., Goc, R., Yay, A. (2021). Use of selenium to ameliorate doxorubicin induced hepatotoxicity by targeting pro-inflammatory cytokines. Biotech Histochem, 96,67-75.
• Di Stefano, G., Fiume, L., Domenicali, M., Busi, C., Chieco, P., Kratz, F., Lanza, M., Mattioli, A., Pariali, M., Bernardi, M. (2006). Doxorubicin coupled to lactosaminated albumin: effects on rats with liver fibrosis and cirrhosis. Dig. Liver Dis, 38, 404–408.
• El-Sayyad, H. I., Ismail, M. F., Shalaby, F. M., Abou-El-Magd, R. F., Gaur, R. L., Fernando, A., Raj, M. H., Ouhtit, A. (2009). Histopathological effects of cisplatin, doxorubicin and 5-flurouracil (5-FU) on the liver of male albino rats9”. International journal of biological sciences, 5, 466–473.
• Gazdic, M., Simovic Markovic, B., Vucicevic, L., et al. (2018). Mesenchymal stem cells protect from acute liver injury by attenuating hepatotoxicity of liver natural killer T cells in an inducible nitric oxide synthase‐ and indoleamine 2,3‐dioxygenase‐dependent manner. J Tissue Eng Regen Med. 12: e1173– e1185.
• Iqubala, A., Iqubalb, M.K., Haquea, S.E. (2016). Experimental hepatotoxicity Inducing agents: A Review. International Journal of Pharmacological Research 6, 11.
• Jacevic, V., Djordjevic, A., Srdjenovic, B., Milic-Tores, V., Segrt, Z., Dragojevic-Simic, V., Kuca, K. (2017). Fullerenol nanoparticles prevents doxorubicin-induced acute hepatotoxicity in rats. Exp. Mol. Pathol. 102, 360–369.
• Jang, Y.O., Kim, Y.J., Baik, S.K., et al. (2014). Histological improvement following administration of autologous bone marrow-derived mesenchymal stem cells for alcoholic cirrhosis: a pilot study. Liver Int, 34,33-41.
• Kim G., Eom Y.W., Baik S.K., Shin Y., Lim Y.L., Kim M.Y., Kwon S.O., Chang S.J. (2015). Therapeutic Effects of Mesenchymal Stem Cells for Patients with Chronic Liver Diseases: Systematic Review and Meta-analysis. J Korean Med Sci. 30,10,1405-15.
• Kuo, T.K., Hung, S.P., Chuang, C.H., Chen, C.T., Shih, Y.R., Fang, S.C., et al. (2008). Stem cell therapy for liver disease: parameters governing the success of using bone marrow mesenchymal stem cells. Gastroenterology, 134, 2111-2121.
• Luo, X., Gupta, K., Ananthanarayanan, A., Wang, Z., Xia, L., et al. (2018). Directed Differentiation of Adult Liver Derived Mesenchymal Like Stem Cells into Functional Hepatocytes. Scientific Reports, 8(1).
• Luna L.G. (1968). Manual of histologic staining methods of the armed forces institute of pathology (3rd Ed.) pp. 111–112. New York: McGraw-Hill,
• Mansouri, E., Jangaran, A., Ashtari, A. (2017). Protective effect of pravastatin on doxorubicin-induced hepatotoxicity. Bratislavske Lekarske Listy, 118,5:273-277.
• Öz, M., Yavuz, O., Bölükbaş, F. (2020). Histopathology changes in the rainbow trout (Onchorhyncus mykiss) consuming boric acid supplemented fish fodder. Journal of Trace Elements in Medicine and Biology. 62, 126581.
• Prasanna, P.L., Kaviyarasi R., Abilash V.G. (2020). New molecular and biochemical insights of doxorubicin-induced hepatotoxicity. Life sciences, 250, 117599.
• Pugazhendhi, A., Edison, T.N.J.I., Velmurugan, B.K., Jacob, J.A., Karuppusamy, I. (2018). Toxicity of Doxorubicin (Dox) to different experimental organ systems. Life Sci, 200, 26-30.
• Qureshi, A., Pervez, S. (2010). Allred scoring for ER reporting and it's impact in clearly distinguishing ER negative from ER positive breast cancers. Journal Pakistan Medical Association, 60, 350-353.
• Ramanathan, R., Rupert, S., Selvaraj, S., Satyanesan, J., Vennila, R., Rajagopal, S. (2017). Role of Human Wharton’s Jelly Derived Mesenchymal Stem Cells (WJ-MSCs) for Rescue of d -Galactosamine Induced Acute Liver Injury in Mice. Journal of Clinical and Experimental Hepatology, 7, 3, 205–214.
• Shivakumar, P., Rani, M.U., Reddy, A.G., Anjaneyulu, Y. (2012). A study on the toxic effects of doxorubicin on the histology of certain organs. Toxicol. Int. 19, 241–244.
• Singh, G., Dhadwal, N., Harikumar, S.L. (2015). Experimental Models For Hepatotoxicity. Asian J Pharm Clin Res, 8, 2, 70-74.
• Singh, R., Kumar, S., Rana, A.C., Sharma, N. (2012). Different models of hepatotoxicity and related liver diseases: A review. Int Res J Pharmacy. 3, 764-769.
• Supriya, R., Tam, B.T., Pei, X.M., Lai, C.W., Chan, L.W., Yung, B.Y., Siu, P.M. (2016). Doxorubicin induces inflammatory modulation and metabolic dysregulation in diabetic skeletal muscle. Front Physiol, 7, 323–336.
• Wang, L., Chen, Q., Qi, H., Wang, C., Wang, C., Zhang, J., Dong, L. (2016). Doxorubicin-induced systemic inflammation is driven by upregulation of toll-like receptor TLR4 and endotoxin leakage. Cancer Res, 76, 6631–6642.
• Yu, Y., Yao, A.H., Chen, N., Pu, L.Y., Fan, Y., Lv, L., Sun, B.C., Li, G.Q., Wang, X.H. (2007). Mesenchymal stem cells over-expressing hepatocyte growth factor improve small-for-size liver grafts regeneration. Mol Ther, 15,1382-1389.