Addressing the liver progenitor cell response and hepatic oxidative stress in experimental non-alcoholic fatty liver disease/non-alcoholic steatohepatitis using amniotic epithelial cells

Stem Cell Research & Therapy

Gregory Moore¹  William Sievert¹  Nathan Kuk¹  Alex Hodge¹  Mihiri Goonetilleke²  Jeanne Correia³  George Yeoh⁴  Michael P. Gantier⁵  Rebecca Lim⁶ 

[1] Centre for Inflammatory Disease, School of Clinical Sciences, Monash University, Melbourne, Victoria, Australia;Gastroenterology and Hepatology Unit, Monash Health, Melbourne, Victoria, Australia;Centre for Inflammatory Disease, School of Clinical Sciences, Monash University, Melbourne, Victoria, Australia;The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Victoria, Australia;Centre for Inflammatory Disease, School of Clinical Sciences, Monash University, Melbourne, Victoria, Australia;The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Victoria, Australia;Gastroenterology and Hepatology Unit, Monash Health, Melbourne, Victoria, Australia;Centre for Medical Research, Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, Western Australia, Australia;School of Molecular Sciences, The University of Western Australia, Crawley, Western Australia, Australia;Centre for Cell Therapy and Regenerative Medicine, School of Biomedical Sciences, The University of Western Australia, Crawley, Western Australia, Australia;Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia;Centre for Innate Immunity and Infectious Disease, Hudson Institute of Medical Research, Melbourne, Victoria, Australia;The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Victoria, Australia;Department of Obstetrics and Gynaecology, Monash University, Melbourne, Victoria, Australia;

关键词: Fatty liver disease;    NASH/NAFLD;    Liver progenitor cells;    Hepatic oxidative stress;    Amnion epithelial cells;    Regenerative medicine;   

DOI  :  10.1186/s13287-021-02476-6

来源: Springer

【 摘 要 】

BackgroundNon-alcoholic fatty liver disease is the most common liver disease globally and in its inflammatory form, non-alcoholic steatohepatitis (NASH), can progress to cirrhosis and hepatocellular carcinoma (HCC). Currently, patient education and lifestyle changes are the major tools to prevent the continued progression of NASH. Emerging therapies in NASH target known pathological processes involved in the progression of the disease including inflammation, fibrosis, oxidative stress and hepatocyte apoptosis. Human amniotic epithelial cells (hAECs) were previously shown to be beneficial in experimental models of chronic liver injury, reducing hepatic inflammation and fibrosis. Previous studies have shown that liver progenitor cells (LPCs) response plays a significant role in the development of fibrosis and HCC in mouse models of fatty liver disease. In this study, we examined the effect hAECs have on the LPC response and hepatic oxidative stress in an experimental model of NASH.MethodsExperimental NASH was induced in C57BL/6 J male mice using a high-fat, high fructose diet for 42 weeks. Mice received either a single intraperitoneal injection of 2 × 106 hAECs at week 34 or an additional hAEC dose at week 38. Changes to the LPC response and oxidative stress regulators were measured.ResultshAEC administration significantly reduced the expansion of LPCs and their mitogens, IL-6, IFNγ and TWEAK. hAEC administration also reduced neutrophil infiltration and myeloperoxidase production with a concurrent increase in heme oxygenase-1 production. These observations were accompanied by a significant increase in total levels of anti-fibrotic IFNβ in mice treated with a single dose of hAECs, which appeared to be independent of c-GAS-STING activation.ConclusionsExpansion of liver progenitor cells, hepatic inflammation and oxidative stress associated with experimental NASH were attenuated by hAEC administration. Given that repeated doses did not significantly increase efficacy, future studies assessing the impact of dose escalation and/or timing of dose may provide insights into clinical translation.

【 授权许可】

CC BY