Mesenchymal stem cells ameliorate oxidative stress, inflammation, and hepatic fibrosis via Nrf2/HO-1 signaling pathway i
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RESEARCH ARTICLE
Mesenchymal stem cells ameliorate oxidative stress, inflammation, and hepatic fibrosis via Nrf2/HO-1 signaling pathway in rats Sally M. Khadrawy 1 & Hanaa M. Mohamed 1 & Ayman M. Mahmoud 2 Received: 12 May 2020 / Accepted: 25 August 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Liver fibrosis occurs in most types of chronic liver diseases and can develop into cirrhosis and liver failure. Bone marrow-derived mesenchymal stem cells (BMSCs) showed promising effects in the treatment of fibrosis. This study evaluated the possible role of Nrf2/HO-1 signaling in the ameliorative effect of BMSCs against carbon tetrachloride (CCl4)-induced liver fibrosis, oxidative stress, and inflammation in rats. Hepatic fibrosis was induced by subcutaneous injection of CCl4 twice per week for 6 consecutive weeks and rat BMSCs were administered intravenously. After 4 weeks, the rats were sacrificed, and samples were collected for analysis. CCl4-intoxicated rats showed elevated serum transaminases, ALP, γGT, bilirubin and pro-inflammatory cytokines, and decreased albumin. Hepatic NF-κB p65 and malondialdehyde (MDA) were significantly increased, and cellular antioxidants were decreased in CCl4-intoxicated rats. BMSCs ameliorated liver function markers, suppressed MDA, NF-κB p65, and inflammatory cytokines, and enhanced antioxidants in the liver of CCl4-intoxicated rats. BMSCs were engrafted within the liver tissue and prevented histological alterations and collagen accumulation induced by CCl4. In addition, BMSCs upregulated hepatic Nrf2 and HO-1 expression in CCl4-intoxicated rats. In conclusion, this study provides evidence that BMSCs suppress oxidative stress, inflammation, and liver fibrosis through a mechanism involving activation of the Nrf2/HO-1 signaling. Keywords Liver fibrosis . Oxidative stress . Nrf2 . Stem cells . Cell therapy
Introduction Chronic liver diseases are characterized by progressive deterioration of liver function and represent a significant problem worldwide with socioeconomic burden. The number of people suffering from chronic liver diseases has been estimated to exceed 800 million with 2 million deaths every year (Marcellin and Kutala 2018). Long-term hepatocyte injury provokes the loss of liver function and the excessive deposition of extracellular matrix (ECM), leading to the development of fibrogenesis. Hepatic fibrogenesis is a complex and multifactorial process characterized by inflammation and
Responsible editor: Mohamed M. Abdel-Daim * Ayman M. Mahmoud [email protected] 1
Genetics Division, Zoology Department, Faculty of Science, Beni-Suef University, Beni-Suef, Egypt
2
Physiology Division, Zoology Department, Faculty of Science, Beni-Suef University, Beni-Suef, Egypt
accumulation of ECM rich in collagen (Friedman 2008b), and can develop into an advanced stage of scarring and damage known as cirrhosis and hepatocellular carcinoma (HCC) (Tacke and Trautwein 2015). In chronic liver diseases, the excessive ECM is produced by the active hepat
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