Combination of cord blood-derived human hepatic progenitors and hepatogenic factors strongly improves recovery after acute liver injury in mice through modulation of the Wnt/?-catenin signaling

Cell therapy represents the promising alternative strategy for end-stage liver disease, and hepatic progenitors are the best candidates. The possibility to maximize the paracrine effects of transplanted cells represents a great potential benefit for cell therapy success. We studied how cell type and microenvironment modulate the Wnt/?-catenin signaling in vitro and in vivo. In vitro, the onset of hepatocyte commitment was characterized by the presence of nuclear truncated ?-catenin. In vivo, we analyzed the effect of human hepatic progenitors on damage recovery and functional regeneration in a mouse model of acute liver injury, either in combination or in absence of a selected mix of hepatogenic factors. Animals injected with human hepatic progenitors and hepatogenic factors showed improved engraftment triggering the Wnt/?-catenin signaling cascade. Human hepatic progenitors expressing the human oval cell marker OV6 displayed a consistent co-localization with ?-catenin and co-localized with Wnt1 main ligand of the canonical pathway. Wnt5a, on the contrary, was expressed in distinct liver cell populations. Epithelial mesenchymal transition-related markers showed enhanced expression and wider distribution and the hepato-mesenchymal population Thy1+CK19- was also present. Control animals injected with hepatogenic factors alone exhibited higher ?-catenin and decreased Wnt5a levels, and persistent proliferation of the hepato-mesenchymal population. In conclusion, the combination of human hepatic progenitors with selected hepatogenic factors creates a positive synergy with local microenvironment, ameliorates cell engraftment, stimulates and accelerates regenerative process and improves the rescue of hepatic function, by modulating the Wnt/?catenin signaling and activating hepato-mesenchymal population.