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24 September 2019 : Animal Research  

Effects of Bone Marrow-Derived Mesenchymal Stem Cells on Hypoxia and the Transforming Growth Factor beta 1 (TGFβ-1) and SMADs Pathway in a Mouse Model of Cirrhosis

Liting Zhang12ABCDEFG, Dan Zhou3BCDEF, Junfeng Li4CDG, Xiaoming Yan5BCD, Jun Zhu6BD, Ping Xiao4D, Tuo Chen1AE, Xiaodong Xie7AE*

DOI: 10.12659/MSM.916428

Med Sci Monit 2019; 25:7182-7190

Abstract

BACKGROUND: The role of bone marrow-derived mesenchymal stem cells (BM-MSCs) in liver fibrosis remains poorly understood. This study aimed to use a mouse model of carbon tetrachloride (CCL₄)-induced liver fibrosis to investigate the effects of BM-MSCs during liver hypoxia and the involvement of the transforming growth factor beta 1 (TGF-β1) and SMADs pathway.

MATERIAL AND METHODS: Thirty C57BL/6 mice were randomly divided into the control group (n=10), the model group (n=10), and the BM-MSC-treated model group (n=10). In the model group, liver fibrosis was induced by intraperitoneal injection of CCl₄. BM-MSCs were transplanted after 12 weeks of CCl₄ treatment. The serum biochemical parameters and histological changes in the liver, using histochemical stains, were investigated. The expression of collagen type I (collagen I), alpha-smooth muscle actin (α-SMA), TGF-β1, SMAD3, SMAD7, hypoxia-inducible factor 1 alpha (HIF-1α), and vascular endothelial grow factor (VEGF) were assessed by immunohistochemistry and quantitative real-time polymerase chain (RT-qPCR) reaction.

RESULTS: Treatment with BM-MSCs reduced the expression of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) compared with the model group, and reduced liver fibrosis determined histologically using hematoxylin and eosin (H&E) and Masson’s trichrome staining compared with the model group. The area of liver fibrosis decreased after BM-MSCs treatment (p<0.05). Protein expression of HIF-1α and VEGF were decreased after BM-MSCs treatment (p<0.05). Transplantation of BM-MSCs reduced the mRNA expression of TGF-β1, collagen I, α-SMA, and SMAD3 (p<0.05).

CONCLUSIONS: BM-MSC transplantation reduced CCl₄-induced murine liver fibrosis, indicating that in a hypoxic microenvironment, BM-MSCs may inhibit the TGFβ-1/SMADs pathway.

Keywords: Cell Hypoxia, Liver Cirrhosis, Experimental, mesenchymal stromal cells, Alanine Transaminase, Aspartate Aminotransferases, Bone Marrow, Carbon Tetrachloride, Fibrosis, Hypoxia-Inducible Factor 1, alpha Subunit, Liver, Liver Cirrhosis, Mesenchymal Stem Cell Transplantation, Smad Proteins, Transforming Growth Factor beta

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Medical Science Monitor eISSN: 1643-3750
Medical Science Monitor eISSN: 1643-3750