Wnt Pathway Activation by Placental Mesenchymal Stem Cells Promotes Hepatic Regeneration in a Cirrhotic Rat Model

Abstract Background: Sinusoidal endothelial cells (SECs) in liver play important roles in hepatocyte regeneration. We recently reported placenta-derived mesenchymal stem cells (PD-MSCs) can promote hepatic regeneration in a damaged liver model via dynamic events. However, the effects of PD-MSCs on vascular structure in liver tissues remain unknown. We therefore investigated alteration of vascular structure and function in carbon tetrachloride (CCl4)-injured rat model following transplantation (Tx) with PD-MSCs. Methods: PD-MSCs were engrafted into CCl4-injured rat model via intravenous Tx. Expression markers related to angiogenic factors and Wnt signaling pathway were analyzed by quantitative real time-PCR, Western blot, and immunofluorescence in vitro and in vivo. Furthermore, endothelial permeability assay was performed to confirm the effect of PD-MSCs on the functional regeneration of injured endothelial cells in vitro co-culture system.Results: PD-MSCs were found to significantly reduce the expanded hepatic vein diameter and increased tube formation of the aorta in both in vitro and ex vivo co-culture systems. PD-MSCs also increased the expression of angiogenic factors and activated the Wnt signaling pathway. Furthermore, PD-MSCs reduced endothelial permeability via activation of β-catenin in the in vitro co-culture system. Conclusions: Taken together, PD-MSCs transplantation (PD-MSC Tx) improves the structure and function of SECs by activating Wnt signaling, which triggers hepatic regeneration, in a CCl4-injured rat model. Therefore, these findings suggest that vascular restoration induced by PD-MSCs supports liver regeneration in a hepatic failure model and can be applied as a cell-based therapy.