HGF-modified dental pulp stem cells suppress hepatic Serpine1 and ameliorate concanavalin A-induced acute T cell-mediated hepatitis

Mesenchymal stem cell therapy shows promise for ConA-induced acute T cell-mediated hepatitis, yet its therapeutic effect remains far from satisfactory due to limited hepatic homing and poorly defined molecular mechanisms. The aim of this study is to investigate whether hepatocyte growth factor (HGF) modification can enhance the therapeutic efficacy of dental pulp stem cells (DPSCs) and elucidate the underlying molecular targets. We generated HGF-overexpressing DPSCs and evaluated their therapeutic effects on ConA-induced acute T cell-mediated hepatitis in mice. Integrated transcriptomic and proteomic profiling identified molecular targets, which were validated through immunofluorescence and western blotting. A possible HGF-Serpine1 association was examined by molecular docking and co-immunoprecipitation, and Serpine1 concentration was measured with or without c-Met blockade. Loss-of-function experiments were performed by knocking down the expression of HGF in DPSCs and by generating liver-targeted Serpine1-knockdown mice using AAV8-TBG-siSerpine1 to assess in vivo functional dependence. HGF-modified DPSCs (DPSC-HGF) alleviated hepatic injury and inflammation with more liver-specific homing than unmodified cells. Integrated transcriptomic-proteomic analysis revealed Serpine1 as one of the most consistently regulated molecules across ConA model and treatment groups. Serpine1 knockdown reduced inflammatory cytokine expression, whereas exogenous Serpine1 aggravated but did not initiate ConA-induced injury, indicating its role as a disease-responsive amplifier of inflammation rather than an independent initiator. Molecular studies supported a possible HGF–Serpine1 association. Functional studies supported the importance of this axis: HGF knockdown in DPSCs abolished most of the therapeutic efficacy, and liver-specific Serpine1 knockdown using AAV8-TBG-siSerpine1 markedly attenuated the additional anti-inflammatory benefit of DPSC-HGF, indicating that hepatic Serpine1 is one of major mediators of DPSC-HGF’s therapeutic action. In NCTC1469 cells, DPSC-HGF CM treatment lowered Serpine1 levels, while this difference was not observed after anti-c-MET antibody pre-treated, a pattern consistent with possible c-Met involvement. This study identifies Serpine1 as an important pathogenic amplifier in ConA-induced hepatitis and demonstrates that HGF modification enhances the therapeutic effects of DPSCs, with improved hepatic homing and reduced hepatic Serpine1 expression observed as parallel findings. The findings support further evaluation of HGF-modified DPSCs in ConA-induced acute T cell-mediated hepatitis.