Bone marrow (BM)-derived CD45 (BM45) cells were demonstrated to exhibit an improved antifibrotic effect on the treatment of CCL4-induced liver fibrosis by significantly increasing the level of matrix metalloproteinase 9 (MMP-9). In this study, we aimed to validate the therapeutic effect of BM45 on the treatment of liver cirrhosis and to further investigate the molecular mechanism underlying the effect of growth arrest-specific transcript 5 (GAS5) on BM45. Accordingly, GAS5 significantly suppressed miR-222 and miR-21 expression but enhanced p27 and MMP-9 expression in HepG2 and LX2 cells. Additionally, GAS5 obstructed transforming growth factor (TGF)-β-induced dysregulation of miR-222, p27, and α-smooth muscle actin (α-SMA) in mice. GAS5 showed a considerable potential to enhance the capability of BM45 in restoring the normal expression of CCL4, miR-222, miR-21, MMP-9, p27, and α-SMA that was dysregulated by alanine aminotransferase (ALT), albumin, and fibrosis. In summary, our study validated the regulatory relationship between miR-21 and MMP-9, as well as between miR-222 and p27. The overexpression of GAS5 upregulated the expression of MMP-9 and p27 via respectively reducing the miR-222 and miR-21 expression, resulting in higher BM45-induced activation of hepatic stellate cells (HSCs). Accordingly, same results were obtained in an animal model, indicating that GAS5 may exert a positive effect on the treatment of BM45 of liver cirrhosis.
Keywords: MMP-9; bone marrow (BM)-derived CD45 cells; growth arrest-specific transcript 5; hepatic stellate cells; liver cirrhosis; miRNA; p27.
© 2020 The Authors.