Natural Killer Cells-Produced IFN-γ 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-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.

• Authors: Lu Li, Zhutian Zeng, Ziping Qi, Xin Wang, Xiang Gao, Haiming Wei, Rui Sun, Zhigang Tian
• Journal: Scientific reports (Sci Rep) Vol. 5 Pg. 13687 (Sep 08 2015) ISSN: 2045-2322 [Electronic] England
• PMID: 26345133 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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