Background Hepatic inflammation is the major risk factor of hepatocellular carcinoma(HCC).However,the underlying mechanism by which hepatic inflammation progresses to HCC is poorly understood.This study was designed t...Background Hepatic inflammation is the major risk factor of hepatocellular carcinoma(HCC).However,the underlying mechanism by which hepatic inflammation progresses to HCC is poorly understood.This study was designed to investigate the role of ETS translocation variant 4(ETV4)in linking hepatic inflammation to HCC.Methods Quantitative real-time PCR and immunoblotting were used to detect the expression of ETV4 in HCC tissues and cell lines.RNA sequencing and luciferase reporter assays were performed to identify the target genes of ETV4.Hepatocyte-specific ETV4-knockout(ETV4fl/fl,alb-cre)and transgenic(ETV4Hep-TG)mice and diethylnitrosamine-carbon tetrachloride(DEN-CCL4)treatment experiments were applied to investigate the function of ETV4 in vivo.The Cancer Genome Atlas(TCGA)database mining and pathological analysis were carried out to determine the correlation of ETV4 with tumor necrosis factor-alpha(TNF-α)and mitogen-activated protein kinase 11(MAPK11).Results We revealed that ETV4 was highly expressed in HCC.High levels of ETV4 predicted a poor survival rate of HCC patients.Then we identified ETV4 as a transcription activator of TNF-αand MAPK11.ETV4 was positively correlated with TNF-αand MAPK11 in HCC patients.As expected,an increase in hepatic TNF-αsecretion and macrophage accumulation were observed in the livers of ETV4Hep-TG mice.The protein levels of TNF-α,MAPK11,and CD68 were significantly higher in the livers of ETV4Hep-TG mice compared with wild type mice but lower in ETV4fl/fl,alb-cre mice compared with ETV4fl/fl mice as treated with DEN-CCL4,indicating that ETV4 functioned as a driver of TNF-α/MAPK11 expression and macrophage accumulation during hepatic inflammation.Hepatocyte-specific knockout of ETV4 significantly prevented development of DEN-CCL4-induced HCC,while transgenic expression of ETV4 promoted growth of HCC.Conclusions ETV4 promoted hepatic inflammation and HCC by activating transcription of TNF-αand MAPK11.Both the ETV4/TNF-αand ETV4/MAPK11 axes represented two potential therapeutic targets for highly associated hepatic inflammation and HCC.ETV4+TNF-αwere potential prognostic markers for HCC patients.展开更多
Stem cell-based and stem cell-derived exosome-based therapies have shown promising potential for endometrial regeneration and the clinical treatment of intrauterine adhesions(IUAs).Evidence shows that apoptosis occurs...Stem cell-based and stem cell-derived exosome-based therapies have shown promising potential for endometrial regeneration and the clinical treatment of intrauterine adhesions(IUAs).Evidence shows that apoptosis occurs in a majority of grafted stem cells,and apoptotic bodies(ABs)play a critical role in compensatory tissue regeneration.However,the therapeutic potential of AB-based therapy and its mechanism have not been explored in detail.Here,a cell-free therapeutic strategy was developed by incorporating mesenchymal stem cell-derived ABs into a hyaluronic acid(HA)hydrogel to achieve endometrial regeneration and fertility restoration.Specifically,we found that the ABs could induce macrophage immunomodulation,cell proliferation,and angiogenesis in vitro.The HA hydrogel promoted the retention of ABs and facilitated their continuous release.In a murine model of acute endometrial damage and a rat model of IUAs,in situ injection of the AB-laden HA hydrogel could efficiently reduce fibrosis and promote endometrial regeneration,resulting in the fertility restoration.Consequently,ABs show good potential as therapeutic vesicles,and the AB-laden HA hydrogel appears to be a clinically feasible and cell-free alternative for endometrial regeneration and IUA treatment.展开更多
Innate lymphoid cells (ILCs) are immune cells newly defined inrecent decades and are recognized as the innate counterpart of theT helper cells, including IFNc-producing group 1 ILCs (ILC1s), IL-5and IL-13-producing gr...Innate lymphoid cells (ILCs) are immune cells newly defined inrecent decades and are recognized as the innate counterpart of theT helper cells, including IFNc-producing group 1 ILCs (ILC1s), IL-5and IL-13-producing group 2 ILCs (ILC2s), and IL-22-producinggroup 3 ILCs (ILC3s). Although with a tiny population, ILCs arenot only required for the host to maintain the tissue homeostasisand defense against pathogen invasion but also actively involvedin various inflammatory and allergic diseases [1]. The immune systemis shaped critically in early life, especially when born preterm.Although the development of the immune system in preterm childrenhas been extensively discussed [2], it is still unknownwhether the development of ILCs is influenced by preterm birth.展开更多
基金National Key R&D Program of China,Grant/Award Numbers:2022YFC2303400,2022YFC2305205Strategic Priority Research Program of the Chinese Academy of Sciences,Grant/Award Number:XDB29010000。
文摘Background Hepatic inflammation is the major risk factor of hepatocellular carcinoma(HCC).However,the underlying mechanism by which hepatic inflammation progresses to HCC is poorly understood.This study was designed to investigate the role of ETS translocation variant 4(ETV4)in linking hepatic inflammation to HCC.Methods Quantitative real-time PCR and immunoblotting were used to detect the expression of ETV4 in HCC tissues and cell lines.RNA sequencing and luciferase reporter assays were performed to identify the target genes of ETV4.Hepatocyte-specific ETV4-knockout(ETV4fl/fl,alb-cre)and transgenic(ETV4Hep-TG)mice and diethylnitrosamine-carbon tetrachloride(DEN-CCL4)treatment experiments were applied to investigate the function of ETV4 in vivo.The Cancer Genome Atlas(TCGA)database mining and pathological analysis were carried out to determine the correlation of ETV4 with tumor necrosis factor-alpha(TNF-α)and mitogen-activated protein kinase 11(MAPK11).Results We revealed that ETV4 was highly expressed in HCC.High levels of ETV4 predicted a poor survival rate of HCC patients.Then we identified ETV4 as a transcription activator of TNF-αand MAPK11.ETV4 was positively correlated with TNF-αand MAPK11 in HCC patients.As expected,an increase in hepatic TNF-αsecretion and macrophage accumulation were observed in the livers of ETV4Hep-TG mice.The protein levels of TNF-α,MAPK11,and CD68 were significantly higher in the livers of ETV4Hep-TG mice compared with wild type mice but lower in ETV4fl/fl,alb-cre mice compared with ETV4fl/fl mice as treated with DEN-CCL4,indicating that ETV4 functioned as a driver of TNF-α/MAPK11 expression and macrophage accumulation during hepatic inflammation.Hepatocyte-specific knockout of ETV4 significantly prevented development of DEN-CCL4-induced HCC,while transgenic expression of ETV4 promoted growth of HCC.Conclusions ETV4 promoted hepatic inflammation and HCC by activating transcription of TNF-αand MAPK11.Both the ETV4/TNF-αand ETV4/MAPK11 axes represented two potential therapeutic targets for highly associated hepatic inflammation and HCC.ETV4+TNF-αwere potential prognostic markers for HCC patients.
基金the funding support by the National Key Research Program of China(2018YFC1004800)the International(Regional)Cooperation and Exchange Program of China(82061160494)+1 种基金the National Natural Science Foundation of China(51873184)the Fundamental Research Funds for the Central Universities(2021FZZX005-16).
文摘Stem cell-based and stem cell-derived exosome-based therapies have shown promising potential for endometrial regeneration and the clinical treatment of intrauterine adhesions(IUAs).Evidence shows that apoptosis occurs in a majority of grafted stem cells,and apoptotic bodies(ABs)play a critical role in compensatory tissue regeneration.However,the therapeutic potential of AB-based therapy and its mechanism have not been explored in detail.Here,a cell-free therapeutic strategy was developed by incorporating mesenchymal stem cell-derived ABs into a hyaluronic acid(HA)hydrogel to achieve endometrial regeneration and fertility restoration.Specifically,we found that the ABs could induce macrophage immunomodulation,cell proliferation,and angiogenesis in vitro.The HA hydrogel promoted the retention of ABs and facilitated their continuous release.In a murine model of acute endometrial damage and a rat model of IUAs,in situ injection of the AB-laden HA hydrogel could efficiently reduce fibrosis and promote endometrial regeneration,resulting in the fertility restoration.Consequently,ABs show good potential as therapeutic vesicles,and the AB-laden HA hydrogel appears to be a clinically feasible and cell-free alternative for endometrial regeneration and IUA treatment.
基金This work was supported by the National Natural Science Foundation of China(31821003,91642106,31570923,and 81901603)the Beijing Natural Science Foundation(S160004 and S170003)+3 种基金the China Postdoctoral Science Foundationsupported by the Tsinghua-Peking Center for Life Sciencesthe Institute for Immunologythe School of Medicine at Tsinghua University。
文摘Innate lymphoid cells (ILCs) are immune cells newly defined inrecent decades and are recognized as the innate counterpart of theT helper cells, including IFNc-producing group 1 ILCs (ILC1s), IL-5and IL-13-producing group 2 ILCs (ILC2s), and IL-22-producinggroup 3 ILCs (ILC3s). Although with a tiny population, ILCs arenot only required for the host to maintain the tissue homeostasisand defense against pathogen invasion but also actively involvedin various inflammatory and allergic diseases [1]. The immune systemis shaped critically in early life, especially when born preterm.Although the development of the immune system in preterm childrenhas been extensively discussed [2], it is still unknownwhether the development of ILCs is influenced by preterm birth.
