Cumulative Effect of Mesenchymal Stem Cells and Heme Oxygenase-1 Inducer in Ameliorating Induced Liver Toxicity in Rats

Document Type: Original Article

Authors

1 Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Cairo University, Cairo, Egypt

2 Forensic Medicine Department, Faculty of Medicine, Cairo University, Cairo, Egypt

3 Lab Technology Department, Faculty of Applied Medical Science, Misr University For Science &Technology, Cairo, Egypt.4Department of Anatomy, College of Medicine, Jouf University, Jouf, Arab Saudi

4 Department of Anatomy, College of Medicine, Jouf University, Jouf, Arab Saudi Department of Anatomy and Embryology, Faculty of Medicine, Cairo University, Cairo, Egypt

5 Department of Pharmcology and Therapeutics, College of Medicine, Jouf University, Jouf, Arab Saudi Department of Medical pharmacology, Faculty of Medicine, Cairo University, Cairo, Egypt

Abstract

Liver diseases are most commonly occurring nowadays, that’s why we are in argent need to develop new strategies in treatment. to evaluate the role of MSCs in regenerating liver cells and to clarify the anti-inflammatory role of HO-1 either alone or as a combined therapy with MSCs. 72 rats were divided into seven groups (n=10 rats/group) as follows, group1: control rats, group 2: CCL4, group 3: CCL4 that received MSCs group 4: CCL4 that received HO-1 inhibitor, group 5: CCL4 that received HO-1 inducer, group 6: CCL4 that received combined MSCs and HO-1 inhibitor , and group 7: CCL4 that received combined MSCs and HO-1 inducer. All groups were evaluated histopathologically with assessment of liver functions. The combined MSCs and HO-1 inducer group showed the highest significant results in ALT (p-value ˂0.05), albumin (p-value ˂0.05), HO-1 activity (p-value ˂0.0001), and genes expression compared to other groups.  This is due to the cumulative anti-inflammatory role of both MSCs and HO-1 together with the ability of MSCs to increase the HO-1 expression with further reduction in inflammation and fibrosis. MSCs and HO-1 inducer provide promising tool in treatment of liver disease.

Keywords


22. Zhang Z.H., Zhu W., Ren H.Z., Zhao X., Wang S., Ma H.C., Shi X.L., 2017. Mesenchymal stem cells increase expression of heme oxygenase-1 leading to anti-inflammatory activity in treatment of acute liver failure. Stem Cell Res Ther.  20; 8(1), 70-76.

23. Yun B. L., Choi J., Kim E., Seok J., Lee H., Yoon J., Kim G., 2017. Human Chorionic Plate-Derived Mesenchymal Stem Cells Restore Hepatic Lipid Metabolism in a Rat Model of Bile Duct Ligation. Stem Cells International. 5180579.

24. Wang Y., Wang J.L., Ma H.C., Tang Z.T., Ding H.R., Shi X.L. 2019. Mesenchymal stem cells increase heme oxygenase 1-activated autophagy in treatment of acute liver failure. Biochem Biophys Res Commun. 15; 508(3), 682-689.

1. Ebrahimi H., Naderian M., Sohrabpour A.A., 2016. New Concepts on Pathogenesis and Diagnosis of Liver Fibrosis; A Review Article. Middle East J Dig Dis. 8(3), 166-178.

2. Weiskirchen R., Weiskirchen S., Tacke F., 2018. Recent advances in understanding liver fibrosis: bridging basic science and individualized treatment concepts. F1000Res. 27, 7-12.

3. Nusrat S., Khan M.S., Fazili J., Madhoun M.F., 2014. Cirrhosis and its complications: evidence-based treatment. World J Gastroenterol. 14;20(18), 5442-60.

4. Benyon R.C., Iredale J.P. 2000. Is liver fibrosis reversible? Gut. 46, 443–446.

5. Eom Y.W., Shim K.Y., Baik S.K., 2015. Mesenchymal stem cell therapy for liver fibrosis. Korean J Intern Med. 30(5), 580–589.

6. Fiore E.J., Domínguez L.M., Bayo J., García M.G., Mazzolini G.D., 2018. Taking advantage of the potential of mesenchymal stromal cells in liver regeneration: Cells and extracellular vesicles as therapeutic strategies. World J Gastroenterol. 21; 24(23), 2427-2440.

7. Lundvig D.M., Immenschuh S., Wagener F.A., 2012. Heme oxygenase, inflammation, and fibrosis: the good, the bad, and the ugly? Front Pharmacol. 7; 3, 81-86.

8. Barikbin R., Neureiter D., Wirth J., Erhardt A., Schwinge D., Kluwe J., Schramm C., Tiegs G., Sass G., 2012. Induction of heme oxygenase 1 prevents progression of liver fibrosis in Mdr2 knockout mice. Hepatology. 55(2), 553-62.

9. Sun D., Song H., Shen Z. 2019. Research progress in mesenchymal stem cells modified by Heme oxygenase 1. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 15; 33(7), 901-906.

10. Abdel Aziz M.T., Atta H.M., Mahfouz S., Fouad H.H., Roshdy N.K., Ahmed H.H., Rashed L.A., Sabry D., Hassouna A.A., Hasan N.M., 2007. Therapeutic potential of bone marrow-derived mesenchymal stem cells on experimental liver fibrosis. Clin Biochem. 40(12):893-9.

11. Wu T., Li J., Li Y., Song H., 2017. Antioxidant and Hepatoprotective Effect of Swertiamarin on Carbon Tetrachloride-Induced Hepatotoxicity via the Nrf2/HO-1 Pathway. Cell Physiol Biochem 41, 2242-2254.

12. Amiri F., Molaei S., Bahadori M., Nasiri F., Deyhim M.R., Jalili M.A., Nourani M.R., Roudkenar M.H. 2016. Autophagy-Modulated Human Bone Marrow-Derived Mesenchymal Stem Cells Accelerate Liver Restoration in Mouse Models of Acute Liver Failure. Iran Biomed J. 20(3), 135-44.

13. Farouk S., Sabet S., Abu Zahra F.A., El-Ghor A.A., 2018. Bone marrow derived-mesenchymal stem cells downregulate IL17A dependent IL6/STAT3 signaling pathway in CCl4-induced rat liver fibrosis. PLoS ONE 13(10), e0206130.

14. Gu Q., Wu Q., Jin M., Xiao Y., Xu J., Mao C., Zhao F., Zhang Y., 2012. Heme oxygenase-1 alleviates mouse hepatic failure through suppression of adaptive immune responses. J Pharmacol Exp Ther. 340(1), 2-10.

15. Sodhi K., Puri N., Favero G., Stevens S., Meadows C., Abraham N.G., Rezzani R., Ansinelli H., Lebovics E., Shapiro J.I., 2015. Fructose Mediated Non-Alcoholic Fatty Liver Is Attenuated by HO-1-SIRT1 Module in Murine Hepatocytes and Mice Fed a High Fructose Diet. PLoS One. 22; 10(6), e0128648.

16. Dechun F., Mukhopadhyay P., Qiu J., Wang H., 2018. Inflammation in Liver Diseases. Mediators of Inflammation. 3927134.

17. Alfaifi M., Eom Y.W., Newsome P.N., Baik S.K., 2018. Mesenchymal stromal cell therapy for liver diseases. J Hepatol. 68(6), 1272-1285.

18. Nussler A.K., Hao L., Knobeloch D., Yao P., Nussler N.C., Wang Z., Liu L., Ehnert S., 2010. Protective role of HO-1 for alcohol-dependent liver damage. Dig Dis. 28(6), 792-8.

19. Amiri F., Molaei S., Bahadori M., Nasiri F., Deyhim M.R., Jalili M.A., Nourani M.R., Roudkenar H.M. 2018. Mesenchymal stem cells accelerate liver regeneration in acute liver failure animal model. Biomedical Research and Therapy. 5(11), 2802-2810.

20. Zhao L., Chen S., Shi X., Cao H., Li L., 2018. A pooled analysis of mesenchymal stem cell-based therapy for liver disease. Stem Cell Res Ther. 21; 9(1), 72-79.

21. Yantian C., Zhang B., Lin R., Wang Q., Wang J., Shen F., 2018. Mesenchymal Stem Cell Transplantation for Liver Cell Failure: A New Direction and Option. Gastroenterology Research and Practice. 9231710.