Overexpression of HNF4α enhances umbilical cord mesenchymal stem cell function to treat acute liver failure in mice through macrophage polarization

Background: Advances in research on stem cell therapy provide new feasible solutions for acute liver failure (ALF) treatment. Recent studies have demonstrated that the expression of hepatocyte nuclear factor 4α (HNF4α) reset within the damaged hepatocytes can restore normal physiological function. This study aimed to determine the role of human umbilical cord mesenchymal stem cells (HuMSCs) overexpressing HNF4α in ALF treatment.Method: We isolated and cultured HuMSCs in vitro, reversed it by lent virus expression HNF4α (hereinafter referred to as HuMSC-HNF4α). HuMSC-HNF4α was intraperitoneally administrated into the mice immediately after exposed to D-galactosamine / lipopolysaccharide (D-galn / LPS). To investigate their effects in ALF, we performed liver histological and serumbiochemical analysis. Macrophages differentiation and cytokines secreted by HuMSCs were evaluated to elucidate its mechanisms.Results: We found HuMSC-HNF4α has more obvious therapeutic effects on ALF than the negative control virus transfected the HuMSCs (HuMSC-CON). In vitro, HuMSC-HNF4α promotes the polarization of liver macrophages (Kupffer cells) to M2 phenotype, inhibits the inflammatory response of macrophages and reduces the levels of inflammatory factors such as TNF-α, IL-1β to reduce liver damage.Conclusion: Our research confirmed that the therapeutic effect of HuMSC-HNF4α on ALF is not the same as the previous passive support but an active intervention on excessive inflammation in the body. This provides new ideas for research and clinical practice in the future.