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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

GKO BM cannot rescue Fah−/− mice after NTBC withdrawal.Fah−/− mice were transplanted with GKO (n = 12) or WT (n = 9) BMCs. (a)Survival rate was monitored, and (b)weight changes in GKO or WT BM-transplanted Fah−/− mice were evaluated 22 weeks after NTBC withdrawal. (c) Total serum bilirubin and ALT levels were detected and (d) Liver tissues were collected for H&E staining 22 weeks after NTBC withdrawal (scale bar, 200 μm).
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f4: GKO BM cannot rescue Fah−/− mice after NTBC withdrawal.Fah−/− mice were transplanted with GKO (n = 12) or WT (n = 9) BMCs. (a)Survival rate was monitored, and (b)weight changes in GKO or WT BM-transplanted Fah−/− mice were evaluated 22 weeks after NTBC withdrawal. (c) Total serum bilirubin and ALT levels were detected and (d) Liver tissues were collected for H&E staining 22 weeks after NTBC withdrawal (scale bar, 200 μm).

Mentions: To address whether IFN-γ played an important role in BMDH generation after BMT, we transplanted IFN-γ–deficient (GKO) BM into Fah−/− mice. Compared to WT BM-transplanted Fah−/− mice that remained healthy after NTBC withdrawal and exhibited a high survival rate, GKO BM-transplanted Fah−/− mice showed marked weight loss and died within 6 months after NTBC withdrawal (Fig. 4a,b); these mice also displayed severe liver dysfunction, with increased total serum bilirubin levels and liver pathology (Fig. 4c,d). Thus, GKO BMCs failed to rescue Fah−/− mice, indicating that IFN-γ was required for BMDH generation after BMT.


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)

GKO BM cannot rescue Fah−/− mice after NTBC withdrawal.Fah−/− mice were transplanted with GKO (n = 12) or WT (n = 9) BMCs. (a)Survival rate was monitored, and (b)weight changes in GKO or WT BM-transplanted Fah−/− mice were evaluated 22 weeks after NTBC withdrawal. (c) Total serum bilirubin and ALT levels were detected and (d) Liver tissues were collected for H&E staining 22 weeks after NTBC withdrawal (scale bar, 200 μm).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f4: GKO BM cannot rescue Fah−/− mice after NTBC withdrawal.Fah−/− mice were transplanted with GKO (n = 12) or WT (n = 9) BMCs. (a)Survival rate was monitored, and (b)weight changes in GKO or WT BM-transplanted Fah−/− mice were evaluated 22 weeks after NTBC withdrawal. (c) Total serum bilirubin and ALT levels were detected and (d) Liver tissues were collected for H&E staining 22 weeks after NTBC withdrawal (scale bar, 200 μm).
Mentions: To address whether IFN-γ played an important role in BMDH generation after BMT, we transplanted IFN-γ–deficient (GKO) BM into Fah−/− mice. Compared to WT BM-transplanted Fah−/− mice that remained healthy after NTBC withdrawal and exhibited a high survival rate, GKO BM-transplanted Fah−/− mice showed marked weight loss and died within 6 months after NTBC withdrawal (Fig. 4a,b); these mice also displayed severe liver dysfunction, with increased total serum bilirubin levels and liver pathology (Fig. 4c,d). Thus, GKO BMCs failed to rescue Fah−/− mice, indicating that IFN-γ was required for BMDH generation after BMT.

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