Natural Killer Cells-Produced IFN-γ Improves Bone Marrow-Derived Hepatocytes Regeneration in Murine Liver Failure Model

Bone-marrow transplantation (BMT) can repopulate the liver through BM-derived hepatocyte (BMDH) generation, although the underlying mechanism remains unclear. Using fumarylacetoacetate hydrolase–deficient ( Fah −/− ) mice as a liver-failure model, we confirmed that BMDHs were generated by fusion of BM-derived CD11b + F4/80 + myelomonocytes with resident Fah −/− hepatocytes. Hepatic NK cells became activated during BMDH generation and were the major IFN-γ producers. Indeed, both NK cells and IFN-γ were required for BMDH generation since WT, but not NK-, IFN-γ–, or IFN-γR1–deficient BM transplantation successfully generated BMDHs and rescued survival in Fah −/− hosts. BM-derived myelomonocytes were determined to be the IFN-γ–responding cells. The IFN-γ–IFN-γR interaction contributed to the myelomonocyte–hepatocyte fusion process, as most of the CD11b + BMDHs in mixed BM chimeric Fah −/− hosts transplanted with a 1:1 ratio of CD45.1 + WT and CD45.2 + Ifngr1 −/− BM cells were of CD45.1 + WT origin. Confirming these findings in vitro , IFN-γ dose-dependently promoted the fusion of GFP + myelomonocytes with Fah −/− hepatocytes due to a direct effect on myelomonocytes; similar results were observed using activated NK cells. In conclusion, BMDH generation requires NK cells to facilitate myelomonocyte–hepatocyte fusion in an IFN-γ–dependent manner, providing new insights for treating severe liver failure.