Ferulic Acid Induces Bone Marrow Mesenchymal Stem Cells to Alleviate the Activation of Hepatic Stellate Cells and Liver Fibrosis via Cytoskeletal Rearrangement Inhibition and Mir-19b-3p Transfer

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.