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

Li L, Zeng Z, Qi Z, Wang X, Gao X, Wei H, Sun R, Tian Z - Sci Rep (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China.

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.

No MeSH data available.


Related in: MedlinePlus

Ifngr1−/− BM cannot restore liver function.Fah−/− mice were transplanted with Ifngr1−/− (n = 15) or WT (n = 10) BMCs, and (a) survival rate was monitored. At week 19 after NTBC withdrawal (NTBC off), (b) livers were grossly evaluated (representative pictures of whole livers are shown), and (c) total serum bilirubin and ALT levels were measured. (d) H&E staining from liver sections to evaluate liver pathology are shown (scale bar, 50 μm).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4561890&req=5

f5: Ifngr1−/− BM cannot restore liver function.Fah−/− mice were transplanted with Ifngr1−/− (n = 15) or WT (n = 10) BMCs, and (a) survival rate was monitored. At week 19 after NTBC withdrawal (NTBC off), (b) livers were grossly evaluated (representative pictures of whole livers are shown), and (c) total serum bilirubin and ALT levels were measured. (d) H&E staining from liver sections to evaluate liver pathology are shown (scale bar, 50 μm).

Mentions: Next, we sought to identify the IFN-γ–responding cells in BM-mediated liver reconstitution. To first distinguish whether the IFN-γ–responding cells were the host hepatocyte or the BM-derived myelomonocytes, Fah−/− mice were transplanted with Ifngr1−/− BM so that the transplanted myeloid-derived cells rather than resident hepatocytes lost responsiveness to IFN-γ. Similar to transplantation with GKO BM, we observed that IFN-γR1–deficient BMT could not rescue survival of Fah−/− mice (Fig. 5a). Ifngr1−/− BM reconstitution also resulted in visible liver atrophy and necrosis (Fig. 5b), increased serum level of total serum bilirubin levels (Fig. 5c), and higher inflammatory cell infiltration into the liver (Fig. 5d) compared to WT BM reconstitution. This result suggested a “BM-intrinsic” requirement for IFN-γ signaling during BMDH generation.


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

Li L, Zeng Z, Qi Z, Wang X, Gao X, Wei H, Sun R, Tian Z - Sci Rep (2015)

Ifngr1−/− BM cannot restore liver function.Fah−/− mice were transplanted with Ifngr1−/− (n = 15) or WT (n = 10) BMCs, and (a) survival rate was monitored. At week 19 after NTBC withdrawal (NTBC off), (b) livers were grossly evaluated (representative pictures of whole livers are shown), and (c) total serum bilirubin and ALT levels were measured. (d) H&E staining from liver sections to evaluate liver pathology are shown (scale bar, 50 μm).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4561890&req=5

f5: Ifngr1−/− BM cannot restore liver function.Fah−/− mice were transplanted with Ifngr1−/− (n = 15) or WT (n = 10) BMCs, and (a) survival rate was monitored. At week 19 after NTBC withdrawal (NTBC off), (b) livers were grossly evaluated (representative pictures of whole livers are shown), and (c) total serum bilirubin and ALT levels were measured. (d) H&E staining from liver sections to evaluate liver pathology are shown (scale bar, 50 μm).
Mentions: Next, we sought to identify the IFN-γ–responding cells in BM-mediated liver reconstitution. To first distinguish whether the IFN-γ–responding cells were the host hepatocyte or the BM-derived myelomonocytes, Fah−/− mice were transplanted with Ifngr1−/− BM so that the transplanted myeloid-derived cells rather than resident hepatocytes lost responsiveness to IFN-γ. Similar to transplantation with GKO BM, we observed that IFN-γR1–deficient BMT could not rescue survival of Fah−/− mice (Fig. 5a). Ifngr1−/− BM reconstitution also resulted in visible liver atrophy and necrosis (Fig. 5b), increased serum level of total serum bilirubin levels (Fig. 5c), and higher inflammatory cell infiltration into the liver (Fig. 5d) compared to WT BM reconstitution. This result suggested a “BM-intrinsic” requirement for IFN-γ signaling during BMDH generation.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China.

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.

No MeSH data available.


Related in: MedlinePlus