Mesenchymal stem cells regulated liver DX5- natural killer cells in acute-on-chronic liver failure

Abstract

Background :Acute-on-chronic liver failure (ACLF) is a severe, life-threatening syndrome with high mortality. Transplantation of Mesenchymal Stem Cells (MSCs) have been shown their efficacy in reducing mortality of ACLF patients in our clinical trials. Unveiling the underlying mechanism of action will improve clinical regime of ACLF. Methods: Flow cytometry was applied to assess frequency and phenotype of peripheral blood natural killer cell (NK) from HBV-ACLF patients during MSCs treatment. An acute-on-chronic liver failure mouse model was established by injection of carbon tetrachloride (CCL4) intraperitoneally. We used flow cytometry to characterize frequency, phenotype, proliferation, cytokine secretion and cell conjugation of NK cells from different sources before and after MSCs treatment. Microscopy was applied to investigate cell-cell contact. Results: Frequency of peripheral blood NK cells from HBV-ACLF patients was upregulated by MSCs infusion, which correlated with hepatitis remission. MSCs infusion rescued ACLF mice efficiently, coinciding with hepatitis remission, liver regeneration and NK cells frequency increase both in blood and liver. Strikingly, NKP46+ DX5-, instead of NKP46+ DX5+ liver NK cells responded well to MSCs. In vitro, MSCs were proved to promote the proliferation and GM-CSF secretion of NKP46+ DX5- liver NK cells specifically, which may be owing to their high cell-cell adhesion. Conclusions: Promoting NKP46+ DX5- liver NK cells proliferation and secreting GM-CSF maybe the new machinery of MSCs’ efficacy in ACLF.