Chromodomain helicase DNA binding protein 7(CHD7),an ATP-dependent chromatin remodeler,plays versatile roles in neurodevelopment.However,the functional significance of its ATPase/nucleosome remodeling activity remains...Chromodomain helicase DNA binding protein 7(CHD7),an ATP-dependent chromatin remodeler,plays versatile roles in neurodevelopment.However,the functional significance of its ATPase/nucleosome remodeling activity remains incompletely understood.Here,we generate genetically engineered mouse embryonic stem cell lines harboring either an inducible Chd7 knockout or an ATPase-deficient missense variant identified in individuals with CHD7-related disorders.Through in vitro neural induction and differentiation assays combined with mouse brain analyses,we demonstrate that CHD7 enzymatic activity is indispensable for gene regulation and neurite development.Mechanistic studies integrating transcriptomic and epigenomic profiling reveal that CHD7 enzymatic activity is essential for establishing a permissive chromatin landscape at target genes,marked by the open chromatin architecture and active histone modifications.Collectively,our findings underscore the pivotal role of CHD7 enzymatic activity in neurodevelopment and provide critical insights into the pathogenic mechanisms of CHD7 missense variants in human diseases.展开更多
AIM: To evaluate the therapeutic effects of bone marrow-derived mesenchymal stem cells(BMSCs) with human urokinase-type plasminogen activator(u PA) on liver fibrosis, and to investigate the mechanism of gene therapy.M...AIM: To evaluate the therapeutic effects of bone marrow-derived mesenchymal stem cells(BMSCs) with human urokinase-type plasminogen activator(u PA) on liver fibrosis, and to investigate the mechanism of gene therapy.METHODS: BMSCs transfected with adenovirusmediated human urokinase plasminogen activator(Adu PA) were transplanted into rats with CCl4-induced liver fibrosis. All rats were sacrificed after 8 wk, and their serum and liver tissue were collected for biochemical, histopathologic, and molecular analyzes. The degree of liver fibrosis was assessed by hematoxylin and eosin or Masson's staining. Western blot and quantitative reverse transcription-polymerase chain reaction were used to determine protein and m RNA expression levels.RESULTS: Serum levels of alanine aminotransferase, aminotransferase, total bilirubin, hyaluronic acid, laminin, and procollagen type Ⅲ were markedly decreased, whereas the levels of serum albumin were increased by u PA gene modified BMSCs treatment. Histopathology revealed that chronic CCl4-treatment resulted in significant fibrosis while u PA gene modified BMSCs treatment significantly reversed fibrosis. By quantitatively analysing the fibrosis area of liver tissue using Masson staining in different groups of animals, we found that model animals with CCl4-induced liver fibrosis had the largest fibrotic area(16.69% ± 1.30%), while fibrotic area was significantly decreased by BMSCs treatment(12.38% ± 2.27%) and was further reduced by u PA-BMSCs treatment(8.31% ± 1.21%). Both protein and m RNA expression of β-catenin, Wnt4 and Wnt5 a was down-regulated in liver tissues following u PA gene modified BMSCs treatment when compared with the model animals.CONCLUSION: Transplantation of u PA gene modified BMSCs suppressed liver fibrosis and ameliorated liver function and may be a new approach to treating liver fibrosis. Furthermore, treatment with u PA gene modified BMSCs also resulted in a decrease in expression of molecules of the Wnt signaling pathway.展开更多
In the present study, we transplanted adipose-derived mesenchymal stem cells into the hippo-campi of APP/PS1 transgenic Alzheimer＇s disease model mice. Immunofluorescence staining revealed that the number of newly ge...In the present study, we transplanted adipose-derived mesenchymal stem cells into the hippo-campi of APP/PS1 transgenic Alzheimer＇s disease model mice. Immunofluorescence staining revealed that the number of newly generated （BrdU＋） cells in the subgranular zone of the dentate gyrus in the hippocampus was signiifcantly higher in Alzheimer＇s disease mice after adipose-de-rived mesenchymal stem cell transplantation, and there was also a significant increase in the number of BrdU＋/DCX＋neuroblasts in these animals. Adipose-derived mesenchymal stem cell transplantation enhanced neurogenic activity in the subventricular zone as well. Furthermore, adipose-derived mesenchymal stem cell transplantation reduced oxidative stress and alleviated cognitive impairment in the mice. Based on these ifndings, we propose that adipose-derived mes-enchymal stem cell transplantation enhances endogenous neurogenesis in both the subgranular and subventricular zones in APP/PS1 transgenic Alzheimer＇s disease mice, thereby facilitating functional recovery.展开更多
基金supported by the Medical Science Data Center at Shanghai Medical College of Fudan Universitysupported by grants from National Natural Science Foundation of China (81974229and 82171167 to W.F.,82330049 to W.Z.)+2 种基金Xiamen Municipal Major Project of High-Quality Development of Health and Wellness Technology Program (2024-GZL-GD06 to W.F.)National Key R&D Program of China (2022YFA0806603 to W.F.)Science and Technology Program of Guangzhou,China (2024A04J4924 to C.H.)
文摘Chromodomain helicase DNA binding protein 7(CHD7),an ATP-dependent chromatin remodeler,plays versatile roles in neurodevelopment.However,the functional significance of its ATPase/nucleosome remodeling activity remains incompletely understood.Here,we generate genetically engineered mouse embryonic stem cell lines harboring either an inducible Chd7 knockout or an ATPase-deficient missense variant identified in individuals with CHD7-related disorders.Through in vitro neural induction and differentiation assays combined with mouse brain analyses,we demonstrate that CHD7 enzymatic activity is indispensable for gene regulation and neurite development.Mechanistic studies integrating transcriptomic and epigenomic profiling reveal that CHD7 enzymatic activity is essential for establishing a permissive chromatin landscape at target genes,marked by the open chromatin architecture and active histone modifications.Collectively,our findings underscore the pivotal role of CHD7 enzymatic activity in neurodevelopment and provide critical insights into the pathogenic mechanisms of CHD7 missense variants in human diseases.
基金Supported by National Natural Science Foundation of ChinaNo.81460114+5 种基金Natural Science Foundation of Guangxi Zhuang Autonomous RegionNo.1355005-3-2 and No.2012GXNSFAA053143Chinese Traditional Medicine Science Foundation of Guangxi Zhuang Autonomous RegionNo.GZPT1238Science Foundation of Guangxi Department of EducationNo.201203YB036 and No.2013LX031
文摘AIM: To evaluate the therapeutic effects of bone marrow-derived mesenchymal stem cells(BMSCs) with human urokinase-type plasminogen activator(u PA) on liver fibrosis, and to investigate the mechanism of gene therapy.METHODS: BMSCs transfected with adenovirusmediated human urokinase plasminogen activator(Adu PA) were transplanted into rats with CCl4-induced liver fibrosis. All rats were sacrificed after 8 wk, and their serum and liver tissue were collected for biochemical, histopathologic, and molecular analyzes. The degree of liver fibrosis was assessed by hematoxylin and eosin or Masson's staining. Western blot and quantitative reverse transcription-polymerase chain reaction were used to determine protein and m RNA expression levels.RESULTS: Serum levels of alanine aminotransferase, aminotransferase, total bilirubin, hyaluronic acid, laminin, and procollagen type Ⅲ were markedly decreased, whereas the levels of serum albumin were increased by u PA gene modified BMSCs treatment. Histopathology revealed that chronic CCl4-treatment resulted in significant fibrosis while u PA gene modified BMSCs treatment significantly reversed fibrosis. By quantitatively analysing the fibrosis area of liver tissue using Masson staining in different groups of animals, we found that model animals with CCl4-induced liver fibrosis had the largest fibrotic area(16.69% ± 1.30%), while fibrotic area was significantly decreased by BMSCs treatment(12.38% ± 2.27%) and was further reduced by u PA-BMSCs treatment(8.31% ± 1.21%). Both protein and m RNA expression of β-catenin, Wnt4 and Wnt5 a was down-regulated in liver tissues following u PA gene modified BMSCs treatment when compared with the model animals.CONCLUSION: Transplantation of u PA gene modified BMSCs suppressed liver fibrosis and ameliorated liver function and may be a new approach to treating liver fibrosis. Furthermore, treatment with u PA gene modified BMSCs also resulted in a decrease in expression of molecules of the Wnt signaling pathway.
基金supported by the National High-Tech Research and Development Program of China(863 Program),No.2012AA020905Tsinghua-Yue-Yuen Medical Sciences Fund,No.20240000514
文摘In the present study, we transplanted adipose-derived mesenchymal stem cells into the hippo-campi of APP/PS1 transgenic Alzheimer＇s disease model mice. Immunofluorescence staining revealed that the number of newly generated （BrdU＋） cells in the subgranular zone of the dentate gyrus in the hippocampus was signiifcantly higher in Alzheimer＇s disease mice after adipose-de-rived mesenchymal stem cell transplantation, and there was also a significant increase in the number of BrdU＋/DCX＋neuroblasts in these animals. Adipose-derived mesenchymal stem cell transplantation enhanced neurogenic activity in the subventricular zone as well. Furthermore, adipose-derived mesenchymal stem cell transplantation reduced oxidative stress and alleviated cognitive impairment in the mice. Based on these ifndings, we propose that adipose-derived mes-enchymal stem cell transplantation enhances endogenous neurogenesis in both the subgranular and subventricular zones in APP/PS1 transgenic Alzheimer＇s disease mice, thereby facilitating functional recovery.
