Author/Authors :
Abd-Allah ، Somia H. Department of Medical Biochemistry and Molecular Biology - School of Medicine - Zagazig University , Khamis ، Tarek Department of Pharmacology - Faculty of Veterinary Medicine - Zagazig University , Samy ، Walaa Department of Medical Biochemistry and Molecular Biology - School of Medicine - Zagazig University , Alsemeh ، Amira Ebrahim Department of Anatomy - Faculty of Medicine - Zagazig University , Abdullah ، Doaa M. Department of Clinical Pharmacology, Faculty of Medicine - Zagazig University , Hussein ، Samia Department of Medical Biochemistry and Molecular Biology - School of Medicine - Zagazig University
Abstract :
Background: The therapeutic effect of mesenchymal stem cells (MSCs) in liver cirrhosis is limited by their entrapment in the pulmonary vessels. Thus, the use of MSC-derived exosomes has become a promising strategy. The current work aimed to compare the role of human umbilical cord blood-MSCs (hUCB-MSCs) and their derived exosomes in the alleviation of liver cirrhosis focusing on the role of miR-23b and miR-221 and their direct effectors in inflammatory and autophagic pathways. Methods: Rats were divided into six groups: normal controls (negative control), liver cirrhosis group (positive control), liver cirrhotic rats that received conditioned media, liver cirrhotic rats that received hUCB-MSCs, cirrhotic rats that received exosomes, and cirrhotic rats that received both hUCB-MSCs and exosomes. The messenger RNA expression of transforming growth factor-β (TGF-β), Matrix metalloproteinase 9 (MMP 9), fibronectin, collagen type-1 (col1), alpha-smooth muscle actin (α-SMA), Suppressor of Mothers Against Decapentaplegic (SMAD) 2 and 7, Beclin, P62, and light chain 3 (LC3) were evaluated by quantitative real-time polymerase chain reaction. Immunohistochemical staining for Beclin, P62, and LC3 was performed. Results: The treatment of cirrhotic rats with hUCB-MSCs, exosomes, or the combination of them significantly downregulated miRNA-221, fibronectin, collagen I, α-SMA, Smad2 (P 0.001, for each), and P62 (P=0.032, P 0.001, P 0.001, respectively). Additionally, the treatment of cirrhotic rats with hUCB-MSCs, exosomes, or the combination of them significantly upregulated mTOR, Beclin, LC3, and Smad7 (P 0.001, for each) and miRNA-23 (P=0.021, P 0.001, P 0.001, respectively).Conclusion: hUCB-MSCs and their derived exosomes ameliorated liver cirrhosis by anti-inflammatory and anti-fibrotic effects besides modulation of autophagy. The exosomes had a better improvement effect either alone or combined with hUCB-MSCs, as proved by improvement in liver function tests, and molecular, histopathological, and immunohistochemical profiles.
Keywords :
stem cells , Exosomes , Liver cirrhosis , Gene expression , MicroRNAs
