Transplantation of Mesenchymal Stem Cell-Derived Hepatocytes Primed with Quercetin Alone or in Combination with Rutin and LiCl Enhances Liver Regeneration

Inhibition of Wnt/β-catenin signaling differentiates mesenchymal stem cells (MSCs) into hepatocytes. However, there is lack of data on whether transplanting these cells can enhance liver regeneration. Additionally, it remains unknown if the flavonoids quercetin and rutin and the clinically used drug lithium chloride (LiCl) can effectively differentiate MSCs into hepatocytes and promote liver regeneration. To address this, the rat bile duct ligation (BDL) fibrosis model was used. Male Wistar rats were surgically ligated. Liver function tests, histological analysis and cell tracking were also conducted to validate liver regeneration. Treatment with quercetin inhibited the Wnt pathway, while rutin and LiCl activated it. Hepatic differentiation was noted in three treatment groups: quercetin, quercetin with rutin and LiCl. We observed that the initial downregulation of the Wnt pathway, followed by its upregulation, facilitated the differentiation of MSCs into hepatocytes. Transplantation of quercetin-treated MSC-derived hepatocytes into the rat BDL fibrosis model resulted in complete restoration of liver function, normalization of elevated systemic liver enzymes and reduction of inflammation and fibrosis. Interestingly, quercetin-treated hepatocytes resulted in enhanced liver regeneration compared to rutin and LiCl. Finally, tracking of labeled hepatocytes confirmed their main localization in the liver. In conclusion, MSC-derived hepatocytes, generated through ex vivo treatment with quercetin, exhibit enhanced liver regeneration. These findings provide a novel ex vivo treatment strategy with flavonoids and the clinically used drug LiCl to achieve enhanced liver regeneration in vivo.