Abstract
Background: Bone marrow mesenchymal stem cells (BMSCs) are effective for treating fibrotic liver. BMSCs contain a variety of proteins and RNAs, which have functions similar to their derived cells, but the specific mechanism is unclear. In a recent study, ferulic acid (FA) was highly effective in treating liver fibrosis. Therefore, we combined BMSCs and FA to treat CCl4-induced fibrosis models. Methods: First, we used BMSCs and FA to treat CCl4-induced fibrosis models and observed their therapeutic effect, investigated the specific mechanism of this combination therapy in liver fibrosis. Second, we created a BMSC/hepatic stellate cell (HSC) co-culture system and used FA to treat activated HSCs. We next used cytochalasin D and angiotensin II to investigate whether BMSCs and FA inactivate HSCs through cytoskeletal rearrangement. MiR-19b-3p was enriched in BMSCs and targeted TGF-β receptor II (TGF-βR2). We transfected miR-19b-3p into HSCs and BMSCs separately and detected whether BMSCs transferred miR-19b-3p to HSCs or inactivated HSCs. Results: We used BMSCs and FA to treat CCl4-induced fibrosis models and found that the combination therapy had better effects than FA or BMSCs alone. The expression of the profibrotic markers α-SMA and COL1-A1 was significantly decreased in HSCs co-cultured with BMSCs and FA treatment. Cytoskeletal rearrangement in HSCs was inhibited, and RhoA/ROCK pathway gene expression was decreased. With angiotensin II treatment, COL1-A1 and a-SMA expression increased, while with cytochalasin D treatment, profibrotic gene expression decreased in HSCs. COL1-A1, α-SMA and RhoA/ROCK pathway genes were decreased in activated HSCs treated with a miR-19b-3p mimic, indicating that miR-19b-3p inactivated HSCs by suppressing RhoA/ROCK signalling. In contrast, profibrotic genes were significantly decreased in BMSCs treated with the miR-19b-3p mimic or a miR-19b-3p inhibitor and FA compared with BMSCs treated with the miR-19b-3p mimic alone.Conclusion: BMSCs attenuated HSC activation and liver fibrosis by inhibiting cytoskeletal rearrangement and delivering miR-19b-3p to activated HSCs, inactivating RhoA/ROCK signaling. FA-based combination therapy showed better inhibitory effects on HSC activation, suggesting that BMSCs and their miRNAs combined with FA are novel antifibrotic therapeutics for treating chronic liver disease.
Advances in research of the reversal of liver fibrosis by transplantation of bone marrow mesenchymal stem cells
