Mechanisms Of Initiation Of Hepatic Vascular Regeneration By Hepatocyte And New Strategy For The Prevention Of Liver Injure

Part ? Hepatocyte dominates LSEC proliferation during liver regeneration through VEGFA and PEDFLiver regeneration is a complex and sequential process involving an intricate network of intercellular cross-talk.However,it remains unclear whether hepatocytes in the residual liver harmonize liver sinusoidal endothelial cells(LSECs)to restore liver regeneration.In this study,we found that,after 70% partial hepatectomy(PHx),dampening hepatocytes proliferation by knockout of hepatocytic Oncostatin M receptor(OSMR)or Met receptor obviously delayed later LSECs proliferation.It indicated that hepatocytes themselves can ignite LSECs regeneration,explaining hepatocyte proliferation prior to LSECs during regeneration.Mechanismly,to validate the cellular sources of the analyzed cytokines,we examined the differential cytokine expression pattern in freshly isolated hepatic cells,including hepatocytes,LSECs,Kupffer cells,and hepatic stellate cells,representively.VEGFA increased but PEDF decreased predominantly in hepatocytes.Administration of VEGFA nentralized antibody or PEDF cytokine during the early phase of regeneration delayed the subsequential proliferation of endothelial cells.Accordingly,conditional knockout of VEGFA or overexpression of PEDF in hepatocytesslow down LSEC proliferation.However,after knockout of VEGFA in LSEC,Kupffer or HSC,LSEC regeneration was not obviously impacted.Given that recruitment of bone marrow(BM)LSEC progenitors is required for normal liver regeneration,CD133 postive endothelial progenitor cells(EPCs)were tracked in wild type mice after partial hepatectomy,which has been transplantated bone marrow from green fluorescent protein(GFP)-transgene mice.After Phx 2 days,some CD133+-GFP EPCs were recruited to the liver and differentiated into LSECs.Alteration of VEGFA and PEDF in hepatocytes affected recruitment of EPCs engraftment into liver and subsequecntial differentiated into LSECs.In conclusion,our data establish hepatocytes as a commander of LSEC regeneration to dominate LSEC proliferation and control hepatovascular regeneration.Part ? Contradictory Effects of Mitochondria and Non-Mitochondria-Targeted Antioxidants on Hepatocarcinogenesis by Altering DNA Repair in MiceConflicting effects of antioxidant supplementation on cancer prevention or promotion is of great concern to healthy people and cancer patients.Despite recent studies about antioxidants accelerating the progression of lung cancer and melanoma,antioxidants may still play a role in cancer prevention.Both tumor and antioxidants types influence the actual efficacy.However,little is known about the impact of different types of antioxidants on primary hepatocellular carcinoma(HCC),including non-mitochondrial-and mitochondrial-targeted antioxidants.Utilizing mouse models of chemical hepatocarcinogenesis,we showed that administration of non-mitochondria-targeted antioxidants N-acetylcysteine(NAC)and the soluble vitamin E analog,Trolox,prevented tumorigenesis,whereas administration of mitochondria-targeted antioxidants SS-31(the mitochondria-targeted peptide)and Mito-Q(a derivative of ubiquinone)facilitated tumorigenesis.RNA sequencing revealed that NAC and SS-31 caused very different changes in the oxidation-reduction state and DNA damage response.In diethylnitrosamine(DEN)-treated primary hepatocytes,NAC and Trolox alleviated DNA damage by activating ataxiatelangiectasia mutated(ATM)/ATM and Rad3-related(ATR)for DNA repair whereas SS-31 and Mito-Q aggravated damage by inactivating them.Interestingly,partial recovery of SS-31-scavengened mitochondrial reactive oxygen species(mt ROS)could alleviate SS-31-aggravated DNA damage.Localization of ATM between mitochondria and nuclei was altered after NAC and SS-31 treatment.Furthermore,blockage of phospho-ATR(p-ATR)led to the recurrence of NAC-ameliorated DEN HCC.In contrast,reactivation of p-ATR blocked SS-31-promoted DEN HCC.Conclusion: These results demonstrate that the type of antioxidants plays a previously unappreciated role in hepatocarcinogenesis and provide a mechanistic rationale for exploring the therapeutic use of antioxidants for liver cancer.