The Up-Regulation of miR-146a and miR-29b via Exosomes Protects Against Liver Fibrosis by Inhibiting the TGF-β/Smad3c Signaling Pathway

被引:2
作者
Asl, Bahar Jaberian [1 ]
Monjezi, Sajad [1 ]
Orak, Ghazal [1 ]
Ghaffari, Fatemeh [1 ]
Bavarsad, Samaneh Salehipour [1 ]
Dinarvand, Negar [1 ]
Khedri, Azam [1 ]
机构
[1] Ahvaz Jundishapur Univ Med Sci, Med Basic Sci Res Inst, Cellular & Mol Res Ctr, Ahvaz, Iran
关键词
Hepatic Stellate Cells; TGF-beta/Smad3; Exosomes; miR-146a/miR-29b; MESENCHYMAL STEM-CELLS; MICRORNA-29B; EXPRESSION; INFECTION;
D O I
10.5812/hepatmon-144095
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
Background: Hepatic fibrosis is characterized by the increased proliferation and activation of hepatic stellate cells. Transforming growth factor-beta (TGF-beta) stimulates these stellate cells, leading to the development of liver fibrosis. MicroRNA-146a and microRNA-29b have been identified as significant regulatory factors in fibrogenesis. Objectives: In this study, we investigated the ability of exosomes to alleviate liver fibrosis by enhancing the antifibrotic effects of miR-146a and miR-29b. Methods: The LX-2 cells were exposed to TGF-beta for 24 hours. Subsequently, the cells were treated with exosomes for an additional24 hours. Following this treatment, the mRNA expression levels of alpha-smooth muscle actin (alpha-SMA), collagen1 alpha, miR-146a,and miR-29b, as well as the protein levels of phosphorylated Smad3 (p-Smad3), were evaluated. Results: The findings revealed a significant elevation in the expression of alpha-SMA (5.37-fold, P < 0.0001) and collagen1 alpha (3.87-fold,P < 0.001) genes, as well as an increase in the levels of p-Smad3 protein (5.87-fold, P < 0.0001) in the presence of TGF-beta. Moreover ,the expression of miR-146a (0.54-fold, P < 0.05) and miR-29b (0.46-fold, P < 0.01) genes exhibited a notable decrease compared to the control group under the influence of TGF-beta. In our investigation, the administration of exosomes effectively mitigated the TGF-beta-induced up-regulation of alpha-SMA (3.26-fold, P < 0.01) and collagen1 alpha (1.76-fold, P < 0.01) genes, as well as the p-Smad3protein (2.86-fold, P < 0.01), in LX-2 cells. Conclusions: Our results suggest that exosomes effectively impede the continuous activation of hepatic stellate cells (HSCs) by enhancing the antifibrotic effects mediated by miR-146a and miR-29b. Moreover, exosomes demonstrate inhibitory effects on the TGF-beta/Smad3 signaling pathway, resulting in decreased extracellular matrix (ECM) accumulation in the context of in vitro liver fibrosis
引用
收藏
页数:11
相关论文
共 38 条
[1]   Extracellular Matrix Secretion by Cardiac Fibroblasts Role of MicroRNA-29b and MicroRNA-30c [J].
Abonnenc, Melanie ;
Nabeebaccus, Adam A. ;
Mayr, Ursula ;
Barallobre-Barreiro, Javier ;
Dong, Xuebin ;
Cuello, Friederike ;
Sur, Sumon ;
Drozdov, Ignat ;
Langley, Sarah R. ;
Lu, Ruifang ;
Stathopoulou, Konstantina ;
Didangelos, Athanasios ;
Yin, Xiaoke ;
Zimmermann, Wolfram-Hubertus ;
Shah, Ajay M. ;
Zampetaki, Anna ;
Mayr, Manuel .
CIRCULATION RESEARCH, 2013, 113 (10) :1138-+
[2]  
Afarin R, 2021, J Isfahan Med Sch., V39, P212, DOI DOI 10.22122/JIMS.V39I619
[3]   Exosomes of Whartons' jelly mesenchymal stem cell reduce the NOX genes in TGF-β-induced hepatic fibrosis [J].
Afarin, Reza ;
Behdarvand, Tahereh ;
Shakerian, Elham ;
Bavarsad, Samaneh Salehipour ;
Rashidi, Mojtaba .
IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES, 2022, 25 (12) :1498-1503
[4]   Hepatocyte mitochondria-derived danger signals directly activate hepatic stellate cells and drive progression of liver fibrosis [J].
An, Ping ;
Wei, Lin-Lin ;
Zhao, Shuangshuang ;
Sverdlov, Deanna Y. ;
Vaid, Kahini A. ;
Miyamoto, Makoto ;
Kuramitsu, Kaori ;
Lai, Michelle ;
Popov, Yury, V .
NATURE COMMUNICATIONS, 2020, 11 (01)
[5]   Interplay between MAPK/ERK signaling pathway and MicroRNAs: A crucial mechanism regulating cancer cell metabolism and tumor progression [J].
Asl, Elmira Roshani ;
Amini, Mohammad ;
Najafi, Souzan ;
Mansoori, Behzad ;
Mokhtarzadeh, Ahad ;
Mohammadi, Ali ;
Lotfinejad, Parisa ;
Bagheri, Mehdi ;
Shirjang, Solmaz ;
Lotfi, Ziba ;
Rasmi, Yousef ;
Baradaran, Behzad .
LIFE SCIENCES, 2021, 278
[6]   TGFβ1-Pretreated Exosomes of Wharton Jelly Mesenchymal Stem Cell as a Therapeutic Strategy for Improving Liver Fibrosis [J].
Bavarsad, Samaneh Salehipour ;
Jalali, Mohammad Taha ;
Nejad, Darioush Bijan ;
Alypoor, Behnam ;
Rezaei, Hossein Babaahmadi ;
Mohammadtaghvaei, Narges .
HEPATITIS MONTHLY, 2022, 22 (01)
[7]   Immune responses of human dental pulp stem cells in lipopolysaccharide-induced microenvironment [J].
Bindal, Priyadarshini ;
Ramasamy, Thamil Selvee ;
Abu Kasim, Noor Hayaty ;
Gnanasegaran, Nareshwaran ;
Chai, Wen Lin .
CELL BIOLOGY INTERNATIONAL, 2018, 42 (07) :832-840
[8]   MicroRNAs, transforming growth factor beta-1, and tissue fibrosis [J].
Bowen, Timothy ;
Jenkins, Robert H. ;
Fraser, Donald J. .
JOURNAL OF PATHOLOGY, 2013, 229 (02) :274-285
[9]   Three-dimensional culture of MSCs produces exosomes with improved yield and enhanced therapeutic efficacy for cisplatin-induced acute kidney injury [J].
Cao, Jingyuan ;
Wang, Bin ;
Tang, Taotao ;
Lv, Linli ;
Ding, Zhaoying ;
Li, Zuolin ;
Hu, Ruoyu ;
Wei, Qing ;
Shen, Anran ;
Fu, Yuqi ;
Liu, Bicheng .
STEM CELL RESEARCH & THERAPY, 2020, 11 (01)
[10]   Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement [J].
Dominici, M. ;
Le Blanc, K. ;
Mueller, I. ;
Slaper-Cortenbach, I. ;
Marini, F. C. ;
Krause, D. S. ;
Deans, R. J. ;
Keating, A. ;
Prockop, D. J. ;
Horwitz, E. M. .
CYTOTHERAPY, 2006, 8 (04) :315-317