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.
Highlights
Liver failure, characterized by massive hepatocyte death and severely impaired liver function, is a major life-threatening condition in patients with hepatitis, drug, or metabolic disorder–induced liver injury[1,2]
In order to begin exploring the mechanism underlying how BM-derived hepatocytes (BMDHs) develop and function to repopulate the liver after BM transplantation (BMT) to treat hepatic failure, Fah−/− mice were transplanted with WT bone marrow cells (BMCs) and monitored for more than 30 weeks after NTBC withdrawal
These BMDHs were likely generated by fusion of donor WT BM-derived myelomonocytes with resident Fah−/− hepatocytes, as they expressed both myelomonocyte markers (CD45, CD11b) and Fah (Fig. 1e and Supplementary Fig. S1)
Summary
Liver failure, characterized by massive hepatocyte death and severely impaired liver function, is a major life-threatening condition in patients with hepatitis-, drug-, or metabolic disorder–induced liver injury[1,2]. BM-derived hepatocytes (BMDHs) were first discovered in the livers of patients that received cross-gender donor BM transplantation (BMT), raising the possibility that donor BMCs could generate hepatocytes to repopulate damaged liver[5] Further investigation into this phenomenon using mouse models determined that BMDH generation occurred through a cell-fusion mechanism between BMCs and resident hepatocytes rather than through direct differentiation from hematopoietic stem cells (HSCs)[7,8]. A more convenient and appropriate tool to investigate the mechanisms underlying BMDH generation may be the fumarylacetoacetate hydrolase– deficient (Fah−/−) mouse model These mice are ideal tools for this purpose because the lack of Fah results in metabolite accumulation that induces hepatocyte apoptosis, eventually leading to spontaneous liver failure if these mice are not supplemented with NTBC (2-[2-nitro-4-tifluoro-methylbenzyol]-1, 3-cyclohexanedione), an agent that blocks HPPDO upstream of Fah and prevents metabolite accumulation[18]. BMT with WT BM could rescue all resident Fah−/− hepatocytes that would normally have died after NTBC withdrawal, allowing us to investigate the mechanisms underlying BMDH generation
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