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.