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

Sci Rep. 2015 Sep 8;5:13687. doi: 10.1038/srep13687.

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-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow Cells / cytology*
  • Bone Marrow Transplantation
  • Cell Fusion
  • Cyclohexanones / adverse effects
  • Disease Models, Animal
  • Female
  • Hepatocytes / cytology*
  • Hepatocytes / physiology*
  • Hydrolases / deficiency
  • Interferon-gamma / biosynthesis*
  • Killer Cells, Natural / immunology
  • Killer Cells, Natural / metabolism*
  • Liver Failure / etiology
  • Liver Failure / metabolism*
  • Liver Failure / mortality
  • Liver Failure / pathology
  • Liver Failure / therapy
  • Liver Regeneration*
  • Male
  • Mice
  • Mice, Knockout
  • Monocytes / metabolism
  • Nitrobenzoates / adverse effects
  • Protein Binding
  • Receptors, Interferon / metabolism

Substances

  • Cyclohexanones
  • Nitrobenzoates
  • Receptors, Interferon
  • interferon gamma receptor
  • Interferon-gamma
  • Hydrolases
  • fumarylacetoacetase
  • nitisinone