Abstract
BACKGROUND: The efficacy of mesenchymal stem cell (MSC)-based therapy for acute liver injury (ALI) involves coordination with the hepatic immune system, a complex and coordinated network of immune-cell interactions. However, studies of the immunomodulatory effects of MSCs have focused on a limited number of cell subsets rather than a systematic assessment. METHODS: Carbon tetrachloride (CCl(4)) was used to induce ALI in mice. To determine the efficacy of MSCs, ALI mice were injected with MSCs via the tail vein, and histopathological changes, survival rate, and the serum levels of liver enzymes were determined. To assess the immune response induced by MSCs, a mass cytometry panel of 43 metal isotope-tagged antibodies was used to characterize the hepatic immune compartment at days 1, 2, 3, and 7 after administration of MSCs or PBS. RESULTS: MSC treatment significantly alleviated CCl(4)-induced ALI and improved the survival rate. MSC treatment also modulated the hepatic immune system in terms of the distribution of immune-cell subsets and the phenotype of single cells. During the injured phase, MSCs inhibited a systemic response by reducing the numbers of Ly6C(low)CD8(+) T(RM) cells, conventional NK cells, and IgM(+)IgD(+) B cells; suppressing the activation of Ly6C(hi)CD8(+) T(RM) cells; downregulating MHC II and IgM expression in IgM(+)IgD(+) B cells; and increasing the number of immunosuppressive monocyte-derived macrophages. During the recovery phase, MSCs promoted the retention of Ly6C(low)CD8(+) T(RM) cells and maintained the immunosuppressive activity of monocyte-derived macrophages. The response to MSC treatment differed between the injured and recovery phases, emphasizing the benefit of dynamic assessment of the immunomodulatory effects of MSCs. CONCLUSIONS: We determined the immunomodulatory effects of MSC treatment on the subtype distribution and phenotypes of hepatic immune cells.