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

ABSTRACT: 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-? producers. Indeed, both NK cells and IFN-? were required for BMDH generation since WT, but not NK-, IFN-?-, or IFN-?R1-deficient BM transplantation successfully generated BMDHs and rescued survival in Fah(-/-) hosts. BM-derived myelomonocytes were determined to be the IFN-?-responding cells. The IFN-?-IFN-?R 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-? 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-?-dependent manner, providing new insights for treating severe liver failure.

SUBMITTER: Li L 

PROVIDER: S-EPMC4561890 | biostudies-other | 2015

REPOSITORIES: biostudies-other