HNF4α overexpression enhances the therapeutic potential of umbilical cord mesenchymal stem/stromal cells in mice with acute liver failure

Abstract

Human umbilical cord mesenchymal stem/stromal cells (hUMSCs) hold promise for treating acute liver failure (ALF). Here, we investigated the therapeutic effect of hUMSCs overexpressing hepatocyte nuclear factor 4a (HNF4a), a transcription factor important for maintaining hepatocyte identity and hepatic functions, in ALF, compared with hUMSCs without overexpression of HNF4a (CON-hUMSCs). The cells were administered into mice via the tail vein for 24 h before exposure to lipopolysaccharide/Dgalactosamine (LPS/D-GalN) for 6 h by intraperitoneal injection. HNF4a-hUMSCs ameliorated liver injury in ALF better than CON-hUMSCs. The overexpression of HNF4a enhanced the transcription of interleukin (IL)-10 and promoted M2 macrophage polarization through the IL-10/signal transducer and activator of transcription 3 (STAT3) pathway. HNF4a-hUMSCs could exert a more pronounced therapeutic effect on ALF than CON-hUMSCs, providing a novel therapy for ALF.

Mesenchymal Stem Cell Therapy in Acute Liver Failure

“…[58][59][60][61] HNF4α overexpression enhances the therapeutic potential of MSCs in ALF mice by promoting the expression of IL-10 and inducing M2 polarization of macrophages. 62 In Con A-induced acute hepatitis mice, MSCs overexpressing IL-35 can reduce the level of interferon gamma (IFN-γ) secreted by liver mononuclear cells through the janus kinase 1 (JAK1)-STAT1/ STAT4 signaling pathway. 63 Human umbilical cord MSCs overexpressing HGF attenuate liver injury and improve survival rate in ALF mice through anti-apoptosis and antioxidation mechanisms.…”

Potential advantages of genetically modified mesenchymal stem cells in the treatment of acute and chronic liver diseases

“…Yu et al [ 88 ] administered human umbilical cord mesenchymal stem cells with overexpressed HNF4α (HuMSC- HNF4α ) to mice with ALF induced by D-galactosamine/lipopolysaccharide (D-galN/LPS). They discovered that HuMSC- HNF4 promoted Kupffer cell polarization to the M2 phenotype, inhibited macrophage inflammatory responses by secreting higher levels of IL-10 and macrophage colony-stimulating factor (M-CSF), and reduced the expression of inflammatory factors such as TNF- and IL-1, which inhibited inflammation and regenerated injuries.…”

The Molecular Regulatory Mechanism in Multipotency and Differentiation of Wharton’s Jelly Stem Cells

“…In WJ-MSCs, overexpression of HNF4A can improve the hepatic differentiation capacity of WJ-MSCs [ 87 ]. Hence, overexpression of HNF4A in WJ-MSCs may be a better choice to treat acute liver failure [ 88 ].…”