Simon Esteva

 Introduction: Liver cirrhosis, the end-stage of chronic liver damage, is the 14^th most common cause of death worldwide with 1.03 million deaths per year and has an increasing morbidity and mortality rate.¹ The development of liver cirrhosis in patients can be linked to alcoholic liver disease, Hepatitis C, Hepatitis B and non-alcoholic steatohepatitis.² Chronic hepatic injury  triggers local inflammation leading to liver fibrogenesis by deposition of collagen which ultimately damages hepatocytes and liver function. Complications usually include ascites, infection, hepatic encephalopathy, liver failure and renal failure.^1,2 Liver transplantation is currently the only therapeutic option in patients who develop hepatic decompensation or hepatocellular carcinoma with cirrhosis.¹ Use of mesenchymal stem cells (MSC) in liver cirrhosis has had promising results as a possible alternative treatment option to transplantation. MSC’s have been shown to have multiple anti-inflammatory and antifibrotic effects by modulating the immune response and microenvironment of the liver.³ The purpose of this research is to investigate which inflammatory mediators are MSCs acting on in the reversal of liver cirrhosis. Methods: Mice had chemically induced liver damage and were treated with MSC. Liver damage was assessed via fibrosis staining and biochemical markers such as TNF- a, IFN- g, AST, ALT and IL-4. Inflammatory mediators such as IL-10 and IL-17 were inhibited in live mice to measure their effects on liver damage with concurrent MSC therapy. Immune cells under investigation such as natural killer (NKT) T cells or T- regulatory (T-reg) cells were also inhibited to understand their effects. Results: MSCs suppress liver damage in an Indoleamine 2,3‐dioxygenase dependent manner. Mice with acute liver damage treated with MSC and 1‐methyl‐dl‐tryptophan (IDO inhibitor) have no improvement in liver damage with a proliferation of NKT and their pro- inflammatory mediators.⁴ Suppression of Interleukin-17 signaling in MSC treated mice reduced liver fibrosis. IL-17 is correlated to the severity of hepatocyte damage and high enough levels are linked to hepatocyte necrosis.  Blocking of the IL-17 signaling pathway can reduce acute hepatitis.⁵ T-regulatory cells and IL-10 have a hepatoprotective role in MSC therapy. Treatment liver fibrotic mice with MSC increases the presence CD4⁺ T-reg cells which secrete IL-10. Depletion of T-reg cells completely inactivates the hepatoprotective events of MSC treatment in mice. Mice with acute liver damage treated with MSC have an increased proliferation of T-reg cells but still have increased fibrotic damage if the production of IL-10 was mitigated.⁶ Conclusion: Studies in mice and humans have shown that transplantation of MSCs have multiple anti-inflammatory effects my modulating the immune response and can lead to a reduction of collagen expression and deposition.  Use of mesenchymal stem cells (MSC) in liver cirrhosis has had promising results in clinical trials as a possible alternative treatment option to transplantation. ³

1. Emmanuel A Tsochatzis, Jaime Bosch, Andrew K Burroughs. Liver Cirrhosis. The Lancet, Volume 383, Issue 9930,2014, Pages 1749-1761. ISSN 0140-6736
2. Detlef Schuppan, Nezam H Afdhal. Liver cirrhosis. The Lancet, Volume 371, Issue 9615, 2008, Pages 838-851,ISSN 0140-6736.
3. Chien-Wei Lee, Yu-Fan Chen, Hao-Hsiang Wu, Oscar K. Lee, Historical Perspectives and Advances in Mesenchymal Stem Cell Research for the Treatment of Liver Diseases. Gastroenterology, Volume 154, Issue 1, 2018, Pages 46-56. ISSN 0016-5085.
4. Gazdic, M, Simovic Markovic, B, Vucicevic, L, et al. 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. 2018; 12: e1173– e1185.
5. Milosavljevic, N., Gazdic, M., Simovic Markovic, B., Arsenijevic, A., Nurkovic, J., Dolicanin, Z., Djonov, V., Lukic, M.L. and Volarevic, V. (2017), Mesenchymal stem cells attenuate acute liver injury by altering ratio between interleukin 17 producing and regulatory natural killer T cells. Liver Transpl, 23: 1040-1050. doi:1002/lt.24784
6. Gazdic, M., Markovic, B.S., Arsenijevic, A., Jovicic, N., Acovic, A., Harrell, C.R., Fellabaum, C., Djonov, V., Arsenijevic, N., Lukic, M.L. and Volarevic, V. (2018), Crosstalk between mesenchymal stem cells and T regulatory cells is crucially important for the attenuation of acute liver injury. Liver Transpl, 24: 687-702. doi:1002/lt.25049