Hepatocyte-like cells derived from human adipose tissue mesenchymal cells partially restore liver function in immunosuppressed mice with ccl4-induced fibrosis

Document Type : Original Research

Authors
1 Department of Clinical Biochemistry,Faculty of Medical Sciences,Tarbiat modares University, Tehran, Iran
2 Department of Clinical Biochemistry,Faculty of Medical Sciences,Tarbiat mranodares University, Tehran,
Abstract
Introduction: Liver diseases are a significant global health burden, causing roughly two million deaths annually. Liver Fibrosis, characterized by excessive extracellular matrix accumulation, is a major contributor to morbidity and mortality. Liver transplantation remains the gold standard for severe Fibrosis, but limitations exist. Cell therapy using Mesenchymal Stem Cells offers a promising alternative. Hepatocyte-like Cells derived from human adipose tissue Mesenchymal Stem Cells are particularly attractive due to their potential for liver regeneration. This study aimed to compare the effectiveness of Mesenchymal stem cells and Hepatocyte-like cells in treating CCl4-induced Liver Fibrosis in immunosuppressed mice. Methods: Twenty C57BL/6 mice were divided into four groups: (1) control, (2) Fibrotic/untreated, (3 Mesenchymal stem cell-treated, (4) Hepatocyte-like cell-treated. Fibrosis was induced in groups 2-4 using intraperitoneal CCl4 injection in immunosuppressed (cyclosporine A) mice. Mesenchymal Stem Cells and Hepatocyte-like Cells were transplanted via tail vein injection in groups 3 and 4, respectively. Liver function tests were measured in all groups. Results: Both Mesenchymal Stem Cells and Hepatocyte-like Cells treatment improved liver function as evidenced by histopathology and biochemical analyses. In the Fibrotic group, Alanine aminotransferase, Aspartate aminotransferase, Alkaline phosphatase, and total bilirubin levels were significantly elevated, while Albumin levels decreased compared to the control group. Following treatment, these parameters significantly improved (p < 0.05) in both treatment groups, suggesting partial regression of Fibrosis. Conclusion: Our findings suggest that both Hepatocyte-like Cells and Mesenchymal Stem Cells have therapeutic potential for moderating Liver Fibrosis regression. However, Mesenchymal Stem Cells therapy may be more cost-effective and time-efficient.

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1. Wang, Z., Y. Song, W. Tu, X. He, J. Lin, and F. Liu, β‐2 Spectrin is involved in hepatocyte proliferation through the interaction of TGF β/Smad and PI 3K/AKT signalling. Liver international, 2012. 32(7): p. 1103-1111.
2. Duncan, A.W., C. Dorrell, and M. Grompe, Stem cells and liver regeneration. Gastroenterology, 2009. 137(2): p. 466-481.
3. Acharya, P., K. Chouhan, S. Weiskirchen, and R. Weiskirchen, Cellular mechanisms of liver fibrosis. Frontiers in Pharmacology, 2021. 12: p. 671640.
4. Roehlen, N., E. Crouchet, and T.F. Baumert, Liver fibrosis: mechanistic concepts and therapeutic perspectives. Cells, 2020. 9(4): p. 875.
5. Asrani, S.K., H. Devarbhavi, J. Eaton, and P.S. Kamath, Burden of liver diseases in the world. Journal of hepatology, 2019. 70(1): p. 151-171.
6. Cho, K.A., S.Y. Ju, S.J. Cho, Y.J. Jung, S.Y. Woo, J.Y. Seoh, et al., Mesenchymal stem cells showed the highest potential for the regeneration of injured liver tissue compared with other subpopulations of the bone marrow. Cell Biology International, 2009. 33(7): p. 772-777.
7. Hardjo, M., M. Miyazaki, M. Sakaguchi, T. Masaka, S. Ibrahim, K. Kataoka, et al., Suppression of carbon tetrachloride-induced liver fibrosis by transplantation of a clonal mesenchymal stem cell line derived from rat bone marrow. Cell transplantation, 2009. 18(1): p. 89-100.
8. Merion, R.M., D.E. Schaubel, D.M. Dykstra, R.B. Freeman, F.K. Port, and R.A. Wolfe, The survival benefit of liver transplantation. American Journal of Transplantation, 2005. 5(2): p. 307-313.
9. Forbes, S.J., S. Gupta, and A. Dhawan, Cell therapy for liver disease: from liver transplantation to cell factory. Journal of hepatology, 2015. 62(1): p. S157-S169.
10. Terai, S. and A. Tsuchiya, Status of and candidates for cell therapy in liver cirrhosis: overcoming the “point of no return” in advanced liver cirrhosis. Journal of gastroenterology, 2017. 52(2): p. 129-140.
11. Bartlett, D.C. and P.N. Newsome, Hepatocyte cell therapy in liver disease. Expert review of gastroenterology & hepatology, 2015. 9(10): p. 1261-1272.
12. Horisawa, K. and A. Suzuki. Cell-Based Regenerative Therapy for Liver Disease. 2015. Tokyo: Springer Japan.
13. Lee, C.A., S. Sinha, E. Fitzpatrick, and A. Dhawan, Hepatocyte transplantation and advancements in alternative cell sources for liver-based regenerative medicine. Journal of Molecular Medicine, 2018: p. 1-13.
14. Haga, J., S. Enosawa, and E. Kobayashi, Cell Therapy for Liver Disease Using Bioimaging Rats. Cell Medicine, 2017. 9(1-2): p. 3-7.
15. Hu, C. and L. Li, In vitro culture of isolated primary hepatocytes and stem cell-derived hepatocyte-like cells for liver regeneration. Protein & cell, 2015. 6(8): p. 562-574.
16. Schwartz, R.E., M. Reyes, L. Koodie, Y. Jiang, M. Blackstad, T. Lund, et al., Multipotent adult progenitor cells from bone marrow differentiate into functional hepatocyte-like cells. The Journal of clinical investigation, 2002. 109(10): p. 1291-1302.
17. Toma, C., M.F. Pittenger, K.S. Cahill, B.J. Byrne, and P.D. Kessler, Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart. Circulation, 2002. 105(1): p. 93-98.
18. Pittenger, M.F., A.M. Mackay, S.C. Beck, R.K. Jaiswal, R. Douglas, J.D. Mosca, et al., Multilineage potential of adult human mesenchymal stem cells. science, 1999. 284(5411): p. 143-147.
19. De Bari, C., F. Dell'Accio, P. Tylzanowski, and F.P. Luyten, Multipotent mesenchymal stem cells from adult human synovial membrane. Arthritis & Rheumatism, 2001. 44(8): p. 1928-1942.
20. Kim, M.-D., S.-S. Kim, H.-Y. Cha, S.-H. Jang, D.-Y. Chang, W. Kim, et al., Therapeutic effect of hepatocyte growth factor-secreting mesenchymal stem cells in a rat model of liver fibrosis. Experimental & molecular medicine, 2014. 46(8): p. e110.
21. Wu, X.-B. and R. Tao, Hepatocyte differentiation of mesenchymal stem cells. Hepatobiliary & Pancreatic Diseases International, 2012. 11(4): p. 360-371.
22. Davoodian, N., A.S. Lotfi, M. Soleimani, and H. Ghaneialvar, The combination of miR‐122 overexpression and Let‐7f silencing induces hepatic differentiation of adipose tissue‐derived stem cells. Cell biology international, 2017. 41(10): p. 1083-1092.
23. Gandomani, M.G., A.S. Lotfi, D.K. Tamandani, S. Arjmand, and S. Alizadeh, The enhancement of differentiating adipose derived mesenchymal stem cells toward hepatocyte like cells using gelatin cryogel scaffold. Biochemical and biophysical research communications, 2017. 491(4): p. 1000-1006.
24. Rabani, V., M. Shahsavani, M. Gharavi, A. Piryaei, Z. Azhdari, and H. Baharvand, Mesenchymal stem cell infusion therapy in a carbon tetrachloride‐induced liver fibrosis model affects matrix metalloproteinase expression. Cell Biology International, 2010. 34(6): p. 601-605.
25. Piryaei, A., M.R. Valojerdi, M. Shahsavani, and H. Baharvand, Differentiation of bone marrow-derived mesenchymal stem cells into hepatocyte-like cells on nanofibers and their transplantation into a carbon tetrachloride-induced liver fibrosis model. Stem Cell Reviews and Reports, 2011. 7(1): p. 103-118.
26. Ewida, S.F., A.G. Abdou, E.-R. Elhosary, A. Abd, E.-G. Metawe, and S. Abd, Hepatocyte-like versus mesenchymal stem cells in CCl4-induced liver fibrosis. Applied immunohistochemistry & molecular morphology, 2017. 25(10): p. 736-745.
27. Huang, B., X. Cheng, H. Wang, W. Huang, Z. la Ga Hu, D. Wang, et al., Mesenchymal stem cells and their secreted molecules predominantly ameliorate fulminant hepatic failure and chronic liver fibrosis in mice respectively. Journal of translational medicine, 2016. 14: p. 1-12.
28. Ewida, S.F., A.G. Abdou, A.A. El-Rasol Elhosary, and S.A. El-Ghane Metawe, Hepatocyte-like versus mesenchymal stem cells in CCl4-induced liver fibrosis. Applied immunohistochemistry & molecular morphology, 2017. 25(10): p. 736-745.
29. Banas, A., T. Teratani, Y. Yamamoto, M. Tokuhara, F. Takeshita, M. Osaki, et al., Rapid hepatic fate specification of adipose‐derived stem cells and their therapeutic potential for liver failure. Journal of gastroenterology and hepatology, 2009. 24(1): p. 70-77.