Mesenchymal Stem Cells Ameliorate Acute-on-Chronic Liver Failure Associated With Expansion of Immunoregulatory Hepatic NKp46+DX5- NK Cells.

BACKGROUND AND AIMS: Hepatitis B virus (HBV)-related acute-on-chronic liver failure (HBV-ACLF) is a life-threatening syndrome characterized by rapid hepatic decompensation and immune dysregulation, with limited treatment options. Mesenchymal stem cells (MSCs) have shown therapeutic potential, but their precise mechanisms-particularly regarding their interaction with hepatic NKp46+DX5- natural killer (NK) cells-remain unexplored. We investigated whether MSC treatment alleviates ACLF, which is associated with the modulation of NK cell populations, and sought to identify key factors driving this immunoregulatory effect.

METHODS

Peripheral NK cells were analyzed in ACLF patients receiving MSC infusion or standard therapy. Flow cytometry assessed NK frequency, phenotype, and correlations with survival. Murine ACLF was induced by carbon tetrachloride (CCL4), followed by MSC treatment. Flow cytometry characterized NK subsets (DX5+/-). In vitro cocultures evaluated MSC-NK interactions, proliferation, and cytokine secretion. NK-MSC conjugation was quantified via live imaging.

RESULTS

Frequency of peripheral blood NK cells from ACLF patients was upregulated after MSCs infusion, which correlated with liver function recovery. Phenotypic changes included upregulation of NKG2A and downregulation of NKp30 and FasL. MSC infusion effectively rescued ACLF mice and increased NK cell frequency in both blood and liver. Strikingly, NKp46+ DX5-, instead of NKp46+ DX5+ hepatic NK cells, responded well to MSCs. In vitro, MSCs promoted proliferation, granulocyte-macrophage colony-stimulating factor (GM-CSF) secretion, and adhesion of NKp46+ DX5- liver NK cells.

CONCLUSIONS

MSC infusion holds significant clinical promise for ACLF patients. In addition to promoting liver regeneration, the immunomodulatory effect of MSCs on hepatic NKp46+DX5- NK cells may provide a novel rationale for refining future therapeutic regimens.