Objective:Myocardial infarction(MI)remains the leading cause of morbidity and mortality due partly to the limited regenerative capacity of cardiomyocytes to replace cardiomyocyte lost due to apoptosis.Inhibiting cardi...Objective:Myocardial infarction(MI)remains the leading cause of morbidity and mortality due partly to the limited regenerative capacity of cardiomyocytes to replace cardiomyocyte lost due to apoptosis.Inhibiting cardiomyocyte apoptosis is recognized as an effective therapeutic approach for MI.MicroRNAs(miRNAs,miRs),which regulate target genes at the post-transcriptional level,play a significant role in the regulation of cardiovascular diseases such as MI.MicroRNA-135b(miR-135b)has a protective effect on cardiomyocytes.However,the role of miR-135b in cardiomyocyte apoptosis in infarct myocardium needs further clarification.Methods:We generatedα-MHC-miR-135b transgenic mice to investigate the role of miR-135b in myocardial injury after MI.MiR-135b mimic and negative control(NC)were transfected into H2O2-induced cardiomyocytes to evaluate the effect of overexpression of miR-135b on the levels of reactive oxygen species(ROS)and apoptosis.Results:Our results showed that overexpression of miR-135b had protective effect on cardiomyocyte injury both in vivo and in vitro.MiR-135b inhibited cardiomyocyte apoptosis and ROS generation,downregulated pro-apoptosis proteins(cleaved-caspase-3 and Bax),and increased anti-apoptosis protein(Bcl-2).Moreover,miR-135b showed an inhibitory effect on apoptosis-related protein target transient receptor potential vanilloid-type 4(TRPV4)cation channel.Conclusion:MiR-135b might be considered a new molecular target for potential replacement therapy as antiapoptotic cardioprotection in the setting of MI.展开更多
BACKGROUND The self-assembly of solid organs from stem cells has the potential to greatly expand the applicability of regenerative medicine.Stem cells can self-organise into microsized organ units,partially modelling ...BACKGROUND The self-assembly of solid organs from stem cells has the potential to greatly expand the applicability of regenerative medicine.Stem cells can self-organise into microsized organ units,partially modelling tissue function and regeneration.Dental pulp organoids have been used to recapitulate the processes of tooth development and related diseases.However,the lack of vasculature limits the utility of dental pulp organoids.AIM To improve survival and aid in recovery after stem cell transplantation,we demonstrated the three-dimensional(3D)self-assembly of adult stem cell-human dental pulp stem cells(hDPSCs)and endothelial cells(ECs)into a novel type of spheroid-shaped dental pulp organoid in vitro under hypoxia and conditioned medium(CM).METHODS During culture,primary hDPSCs were induced to differentiate into ECs by exposing them to a hypoxic environment and CM.The hypoxic pretreated hDPSCs were then mixed with ECs at specific ratios and conditioned in a 3D environment to produce prevascularized dental pulp organoids.The biological characteristics of the organoids were analysed,and the regulatory pathways associated with angiogenesis were studied.RESULTS The combination of these two agents resulted in prevascularized human dental pulp organoids(Vorganoids)that more closely resembled dental pulp tissue in terms of morphology and function.Single-cell RNA sequencing of dental pulp tissue and RNA sequencing of Vorganoids were integrated to analyse key regulatory pathways associated with angiogenesis.The biomarkers forkhead box protein O1 and fibroblast growth factor 2 were identified to be involved in the regulation of Vorganoids.CONCLUSION In this innovative study,we effectively established an in vitro model of Vorganoids and used it to elucidate new mechanisms of angiogenesis during regeneration,facilitating the development of clinical treatment strategies.展开更多
Ageing is often accompanied with a decline in immune system function,resulting in immune ageing.Numerous studies have focussed on the changes in different lymphocyte subsets in diseases and immunosenescence.The change...Ageing is often accompanied with a decline in immune system function,resulting in immune ageing.Numerous studies have focussed on the changes in different lymphocyte subsets in diseases and immunosenescence.The change in immune phenotype is a key indication of the diseased or healthy status.However,the changes in lymphocyte number and phenotype brought about by ageing have not been comprehensively analysed.Here,we analysed T and natural killer(NK)cell subsets,the phenotype and cell differentiation states in 43,096 healthy individuals,aged 20–88 years,without known diseases.Thirty-six immune parameters were analysed and the reference ranges of these subsets were established in different age groups divided into 5-year intervals.The data were subjected to random forest machine learning for immune-ageing modelling and confirmed using the neural network analysis.Our initial analysis and machine modelling prediction showed that na.ve T cells decreased with ageing,whereas central memory T cells(Tcm)and effector memory T cells(Tem)increased cluster of differentiation(CD)28-associated T cells.This is the largest study to investigate the correlation between age and immune cell function in a Chinese population,and provides insightful differences,suggesting that healthy adults might be considerably influenced by age and sex.The age of a person's immune system might be different from their chronological age.Our immune-ageing modelling study is one of the largest studies to provide insights into‘immune-age’rather than‘biological-age’.Through machine learning,we identified immune factors influencing the most through ageing and built a model for immune-ageing prediction.Our research not only reveals the impact of age on immune parameter differences within the Chinese population,but also provides new insights for monitoring and preventing some diseases in clinical practice.展开更多
As a standard cancer treatment method,radiotherapy(RT)has cured or alleviated over half cancer bearing patients worldwide more than 100 years.However,the therapeutic outcome is seriously hindered by the resistant tumo...As a standard cancer treatment method,radiotherapy(RT)has cured or alleviated over half cancer bearing patients worldwide more than 100 years.However,the therapeutic outcome is seriously hindered by the resistant tumor microenvironment(TME).Hypoxia is a critical factor of vicious TME that causes radiation resistance owing to the insufficiency of oxygen for DNA damage maintenance.Moreover,severe vascular dysfunction and pyknomorphic extracellular matrix(ECM)in deep tumor tissues substantially limit radiosensitizer penetration and oxygen diffusion from vessels into tightly packed tumor core.In this study,we develop a hybrid transcytosis nanopomegranate(HTP)with high transcytosis potential in response to TME condition.HTP is architected by self-assembly of small CuS and Au nanoparticles(NPs)at normal physiological condition.HTP can rapidly collapse to transcytosis NPs(CuS and Au NPs)in TME with cationized surface,which enables excellent transcytosis potential and effectively elevates the penetration of CuS and Au into deep tumor tissues.Following the second near-infrared(NIR(II))biowindow laser irradiation,CuS heats the tumor and enhances blood perfusion,eliciting tumor hypoxia alleviation and DNA damage aggravation.Moreover,Au NPs enriched in deep tumor tissues effectively sensitize radio-therapeutic response.Our study provides a new and potential nano-platform to ameliorate tumor hypoxia and sensitize deep tumor tissue radiotherapy.展开更多
Interleukin(IL)-17A,a pro-inflammatory cytokine,is a fundamental function in the onset and advancement of multiple immune diseases.To uncover the primary compounds with IL-17A inhibitory activity,a large-scale screeni...Interleukin(IL)-17A,a pro-inflammatory cytokine,is a fundamental function in the onset and advancement of multiple immune diseases.To uncover the primary compounds with IL-17A inhibitory activity,a large-scale screening of the library of traditional Chinese medicine constituents and microbial secondary metabolites was conducted using splenic cells from IL-17A-GFP reporter mice cultured under Th17-priming conditions.Our results indicated that some aureane-type sesquiterpene tetraketides isolated from a wetland mud-derived fungus,Myrothecium gramineum,showed remarkable IL-17A inhibitory activity.Nine new aureane-type sesquiterpene tetraketides,myrogramins A-I(1,4-11),and two known ones(2 and 3)were isolated and identified from the strain.Compounds 1,3,4,10,and 11 exhibited significant IL-17A inhibitory activity.Among them,compound 3,with a high fermentation yield dosedependently inhibited the generation of IL-17A and suppressed glycolysis in splenic cells under Th17-priming conditions.Strikingly,compound 3 suppressed immunopathology in both IL-17A-mediated animal models of experimental autoimmune encephalomyelitis and pulmonary hypertension.Our results revealed that aureane-type sesquiterpene tetraketides are a novel class of immunomodulators with IL-17A inhibitory activity,and hold great promise applications in treating IL-17A-mediated immune diseases.展开更多
Cardiac fibrosis is one of the crucial pathological factors in the heart,and various cardiac conditions associated with excessive fibrosis can eventually lead to heart failure.However,the exact molecular mechanism of ...Cardiac fibrosis is one of the crucial pathological factors in the heart,and various cardiac conditions associated with excessive fibrosis can eventually lead to heart failure.However,the exact molecular mechanism of cardiac fibrosis remains unclear.In the present study,we show that a novel lnc RNA that we named cardiac fibrosis-associated regulator(CFAR)is a profibrotic factor in the heart.CFAR was upregulated in cardiac fibrosis and its knockdown attenuated the expression of fibrotic marker genes and the proliferation of cardiac fibroblasts,thereby ameliorating cardiac fibrosis.Moreover,CFAR acted as a ce RNA sponge for mi R-449a-5p and derepressed the expression of LOXL3,which we experimentally established as a target gene of mi R-449a-5p.In contrast to CFAR,mi R-449a-5p was found to be significantly downregulated in cardiac fibrosis,and artificial knockdown of mi R-449a-5p exacerbated fibrogenesis,whereas overexpression of mi R-449a-5p impeded fibrogenesis.Furthermore,we found that LOXL3 mimicked the fibrotic factor TGF-β1 to promote cardiac fibrosis by activating m TOR.Collectively,our study established CFAR as a new profibrotic factor acting through a novel mi R-449a-5p/LOXL3/m TOR axis in the heart and therefore might be considered as a potential molecular target for the treatment of cardiac fibrosis and associated heart diseases.展开更多
N6-methyladenosine(m^(6)A),the most common and abundant epigenetic RNA modification,governs mRNA metabolism to determine cell differentiation,proliferation and response to stimulation.m^(6)A methyltransferase METTL3 h...N6-methyladenosine(m^(6)A),the most common and abundant epigenetic RNA modification,governs mRNA metabolism to determine cell differentiation,proliferation and response to stimulation.m^(6)A methyltransferase METTL3 has been reported to control T cell homeostasis and sustain the suppressive function of regulatory T cells(Tregs).However,the role of m^(6)A methyltransferase in other subtypes of T cells remains unknown.T helper cells 17(Th17)play a pivotal role in host defense and autoimmunity.Here,we found that the loss of METTL3 in T cells caused serious defect of Th17 cell differentiation,and impeded the development of experimental autoimmune encephalomyelitis(EAE).We generated Mettl3f/fIl17aCre mice and observed that METTL3 deficiency in Th17 cells significantly suppressed the development of EAE and displayed less Th17 cell infiltration into central nervous system(CNS).Importantly,we demonstrated that depletion of METTL3 attenuated IL-17A and CCR5 expression by facilitating SOCS3 mRNA stability in Th17 cells,leading to disrupted Th17 cell differentiation and infiltration,and eventually attenuating the process of EAE.Collectively,our results highlight that m^(6)A modification sustains Th17 cell function,which provides new insights into the regulatory network of Th17 cells,and also implies a potential therapeutic target for Th17 cell mediated autoimmune disease.展开更多
Idiopathic pulmonary fibrosis(IPF)is a progressive disease with unknown etiology and limited therapeutic options.Activation of fibroblasts is a prominent feature of pulmonary fibrosis.Here we report that lncRNA DACH1(...Idiopathic pulmonary fibrosis(IPF)is a progressive disease with unknown etiology and limited therapeutic options.Activation of fibroblasts is a prominent feature of pulmonary fibrosis.Here we report that lncRNA DACH1(dachshund homolog 1)is downregulated in the lungs of IPF patients and in an experimental mouse model of lung fibrosis.LncDACH1 knockout mice develop spontaneous pulmonary fibrosis,whereas overexpression of LncDACH1 attenuated TGF-β1-induced aberrant activation,collagen deposition and differentiation of mouse lung fibroblasts.Similarly,forced expression of LncDACH1 not only prevented bleomycin(BLM)-induced lung fibrosis,but also reversed established lung fibrosis in a BLM model.Mechanistically,LncDACH1 binding to the serine/arginine-rich splicing factor 1(SRSF1)protein decreases its activity and inhibits the accumulation of Ctnnb1.Enhanced expression of SRSF1 blocked the anti-fibrotic effect of LncDACH1 in lung fibroblasts.Furthermore,loss of LncDACH1 promoted proliferation,differentiation,and extracellular matrix(ECM)deposition in mouse lung fibroblasts,whereas such effects were abolished by silencing of Ctnnb1.In addition,a conserved fragment of LncDACH1 alleviated hyperproliferation,ECM deposition and differentiation of MRC-5 cells driven by TGF-β1.Collectively,LncDACH1 inhibits lung fibrosis by interacting with SRSF1 to suppress CTNNB1 accumulation,suggesting that LncDACH1 might be a potential therapeutic target for pulmonary fibrosis.展开更多
基金supported by CAMS Innovation Fund for Medical Sciences of China(2019-I2M-5-078)National Natural Science Foundation of China(Grant No.81861128022)Natural Science Foundation of Heilongjiang Province(Grant No.LH2019H003).
文摘Objective:Myocardial infarction(MI)remains the leading cause of morbidity and mortality due partly to the limited regenerative capacity of cardiomyocytes to replace cardiomyocyte lost due to apoptosis.Inhibiting cardiomyocyte apoptosis is recognized as an effective therapeutic approach for MI.MicroRNAs(miRNAs,miRs),which regulate target genes at the post-transcriptional level,play a significant role in the regulation of cardiovascular diseases such as MI.MicroRNA-135b(miR-135b)has a protective effect on cardiomyocytes.However,the role of miR-135b in cardiomyocyte apoptosis in infarct myocardium needs further clarification.Methods:We generatedα-MHC-miR-135b transgenic mice to investigate the role of miR-135b in myocardial injury after MI.MiR-135b mimic and negative control(NC)were transfected into H2O2-induced cardiomyocytes to evaluate the effect of overexpression of miR-135b on the levels of reactive oxygen species(ROS)and apoptosis.Results:Our results showed that overexpression of miR-135b had protective effect on cardiomyocyte injury both in vivo and in vitro.MiR-135b inhibited cardiomyocyte apoptosis and ROS generation,downregulated pro-apoptosis proteins(cleaved-caspase-3 and Bax),and increased anti-apoptosis protein(Bcl-2).Moreover,miR-135b showed an inhibitory effect on apoptosis-related protein target transient receptor potential vanilloid-type 4(TRPV4)cation channel.Conclusion:MiR-135b might be considered a new molecular target for potential replacement therapy as antiapoptotic cardioprotection in the setting of MI.
基金Supported by the Science and Technology Programme of Guangzhou City,No.202201020341.
文摘BACKGROUND The self-assembly of solid organs from stem cells has the potential to greatly expand the applicability of regenerative medicine.Stem cells can self-organise into microsized organ units,partially modelling tissue function and regeneration.Dental pulp organoids have been used to recapitulate the processes of tooth development and related diseases.However,the lack of vasculature limits the utility of dental pulp organoids.AIM To improve survival and aid in recovery after stem cell transplantation,we demonstrated the three-dimensional(3D)self-assembly of adult stem cell-human dental pulp stem cells(hDPSCs)and endothelial cells(ECs)into a novel type of spheroid-shaped dental pulp organoid in vitro under hypoxia and conditioned medium(CM).METHODS During culture,primary hDPSCs were induced to differentiate into ECs by exposing them to a hypoxic environment and CM.The hypoxic pretreated hDPSCs were then mixed with ECs at specific ratios and conditioned in a 3D environment to produce prevascularized dental pulp organoids.The biological characteristics of the organoids were analysed,and the regulatory pathways associated with angiogenesis were studied.RESULTS The combination of these two agents resulted in prevascularized human dental pulp organoids(Vorganoids)that more closely resembled dental pulp tissue in terms of morphology and function.Single-cell RNA sequencing of dental pulp tissue and RNA sequencing of Vorganoids were integrated to analyse key regulatory pathways associated with angiogenesis.The biomarkers forkhead box protein O1 and fibroblast growth factor 2 were identified to be involved in the regulation of Vorganoids.CONCLUSION In this innovative study,we effectively established an in vitro model of Vorganoids and used it to elucidate new mechanisms of angiogenesis during regeneration,facilitating the development of clinical treatment strategies.
基金supported by National Key Research and Development Program of China(2020YFA0803502 to Z.Y.)National Natural Science Foundation of China(32030036 and 31830021 to Z.Y.)+6 种基金the 111 Project(B16021 to Z.Y.)Natural Science Foundation of China(81971301 and 32050410285 to O.J.L.)Guangzhou Planned Project of Science and Technology(202002020039 to O.J.L.)Guangdong Basic and Applied Basic Research Foundation(2021A1515110734 to Z.R.)Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology,The First Affiliated Hospital,Sun Yat-sen University,Guangzhou,China(2013A061401007,2017B030314018,2020B1212060026)Guangdong Provincial International Cooperation Base of Science and Technology(Organ Transplantation)The First Affiliated Hospital,Sun Yat-sen University,Guangzhou,China(2015B050501002,2020A0505020003).
文摘Ageing is often accompanied with a decline in immune system function,resulting in immune ageing.Numerous studies have focussed on the changes in different lymphocyte subsets in diseases and immunosenescence.The change in immune phenotype is a key indication of the diseased or healthy status.However,the changes in lymphocyte number and phenotype brought about by ageing have not been comprehensively analysed.Here,we analysed T and natural killer(NK)cell subsets,the phenotype and cell differentiation states in 43,096 healthy individuals,aged 20–88 years,without known diseases.Thirty-six immune parameters were analysed and the reference ranges of these subsets were established in different age groups divided into 5-year intervals.The data were subjected to random forest machine learning for immune-ageing modelling and confirmed using the neural network analysis.Our initial analysis and machine modelling prediction showed that na.ve T cells decreased with ageing,whereas central memory T cells(Tcm)and effector memory T cells(Tem)increased cluster of differentiation(CD)28-associated T cells.This is the largest study to investigate the correlation between age and immune cell function in a Chinese population,and provides insightful differences,suggesting that healthy adults might be considerably influenced by age and sex.The age of a person's immune system might be different from their chronological age.Our immune-ageing modelling study is one of the largest studies to provide insights into‘immune-age’rather than‘biological-age’.Through machine learning,we identified immune factors influencing the most through ageing and built a model for immune-ageing prediction.Our research not only reveals the impact of age on immune parameter differences within the Chinese population,but also provides new insights for monitoring and preventing some diseases in clinical practice.
基金the National Natural Science Foundation of China(Nos.32101139 and 81901888)the Fundamental Research Fund for the Central Universities(No.WK9100000006)+3 种基金the China Postdoctoral Science Foundation(No.2020M683160)the Guangdong Basic and Applied Basic Research Foundation(No.2021A1515220028)the Natural Science Foundation of Anhui Province of China(No.1908085MH247)the University of Science and Technology of China Animal Care and Use Committee(No.USTCACUC1801062).
文摘As a standard cancer treatment method,radiotherapy(RT)has cured or alleviated over half cancer bearing patients worldwide more than 100 years.However,the therapeutic outcome is seriously hindered by the resistant tumor microenvironment(TME).Hypoxia is a critical factor of vicious TME that causes radiation resistance owing to the insufficiency of oxygen for DNA damage maintenance.Moreover,severe vascular dysfunction and pyknomorphic extracellular matrix(ECM)in deep tumor tissues substantially limit radiosensitizer penetration and oxygen diffusion from vessels into tightly packed tumor core.In this study,we develop a hybrid transcytosis nanopomegranate(HTP)with high transcytosis potential in response to TME condition.HTP is architected by self-assembly of small CuS and Au nanoparticles(NPs)at normal physiological condition.HTP can rapidly collapse to transcytosis NPs(CuS and Au NPs)in TME with cationized surface,which enables excellent transcytosis potential and effectively elevates the penetration of CuS and Au into deep tumor tissues.Following the second near-infrared(NIR(II))biowindow laser irradiation,CuS heats the tumor and enhances blood perfusion,eliciting tumor hypoxia alleviation and DNA damage aggravation.Moreover,Au NPs enriched in deep tumor tissues effectively sensitize radio-therapeutic response.Our study provides a new and potential nano-platform to ameliorate tumor hypoxia and sensitize deep tumor tissue radiotherapy.
基金supported by the National Key Research and Development Program of China(2018YFA0903200,2018YFA0903201,and 2020YFA0803502)the National Natural Science Foundation of China(81925037,U22A20371,31830021,32030036,and 82270055)+5 种基金the 111 Project(B16021,China)National High-level Personnel of Special Support Program(2017RA2259,China)Guangdong International Science and Technology Cooperation Base(2021A0505020015,China)Innovative and Research Teams Project of Guangdong Higher Education Institution(2021KCXTD001,China)Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program(2017BT01Y036,China)Guangdong Natural Science Funds for Distinguished Young Scholar(2021B1515020065,China)。
文摘Interleukin(IL)-17A,a pro-inflammatory cytokine,is a fundamental function in the onset and advancement of multiple immune diseases.To uncover the primary compounds with IL-17A inhibitory activity,a large-scale screening of the library of traditional Chinese medicine constituents and microbial secondary metabolites was conducted using splenic cells from IL-17A-GFP reporter mice cultured under Th17-priming conditions.Our results indicated that some aureane-type sesquiterpene tetraketides isolated from a wetland mud-derived fungus,Myrothecium gramineum,showed remarkable IL-17A inhibitory activity.Nine new aureane-type sesquiterpene tetraketides,myrogramins A-I(1,4-11),and two known ones(2 and 3)were isolated and identified from the strain.Compounds 1,3,4,10,and 11 exhibited significant IL-17A inhibitory activity.Among them,compound 3,with a high fermentation yield dosedependently inhibited the generation of IL-17A and suppressed glycolysis in splenic cells under Th17-priming conditions.Strikingly,compound 3 suppressed immunopathology in both IL-17A-mediated animal models of experimental autoimmune encephalomyelitis and pulmonary hypertension.Our results revealed that aureane-type sesquiterpene tetraketides are a novel class of immunomodulators with IL-17A inhibitory activity,and hold great promise applications in treating IL-17A-mediated immune diseases.
基金supported by the National Natural Science Foundation of China(82070240,82073844,82070236,82270246)University Nursing Program for Young Scholars with Creative Talents in Heilongjiang Province(UNPYSCT-2020169)Harbin Medical University Marshal Initiative Funding(HMUMIF-21026)。
文摘Cardiac fibrosis is one of the crucial pathological factors in the heart,and various cardiac conditions associated with excessive fibrosis can eventually lead to heart failure.However,the exact molecular mechanism of cardiac fibrosis remains unclear.In the present study,we show that a novel lnc RNA that we named cardiac fibrosis-associated regulator(CFAR)is a profibrotic factor in the heart.CFAR was upregulated in cardiac fibrosis and its knockdown attenuated the expression of fibrotic marker genes and the proliferation of cardiac fibroblasts,thereby ameliorating cardiac fibrosis.Moreover,CFAR acted as a ce RNA sponge for mi R-449a-5p and derepressed the expression of LOXL3,which we experimentally established as a target gene of mi R-449a-5p.In contrast to CFAR,mi R-449a-5p was found to be significantly downregulated in cardiac fibrosis,and artificial knockdown of mi R-449a-5p exacerbated fibrogenesis,whereas overexpression of mi R-449a-5p impeded fibrogenesis.Furthermore,we found that LOXL3 mimicked the fibrotic factor TGF-β1 to promote cardiac fibrosis by activating m TOR.Collectively,our study established CFAR as a new profibrotic factor acting through a novel mi R-449a-5p/LOXL3/m TOR axis in the heart and therefore might be considered as a potential molecular target for the treatment of cardiac fibrosis and associated heart diseases.
基金supported by the National Natural Science Foundation of China(82230067,82061148013,91842105,81821001)Shanghai Science and Technology Committee(20JC1417400,201409005500)+3 种基金the National Key Research and Development Program of China(2018YFA0508000)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB29030101)the CAS Project for Young Scientists in Basic Research(YSBR-074)the Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment(2021B1212040004).
文摘N6-methyladenosine(m^(6)A),the most common and abundant epigenetic RNA modification,governs mRNA metabolism to determine cell differentiation,proliferation and response to stimulation.m^(6)A methyltransferase METTL3 has been reported to control T cell homeostasis and sustain the suppressive function of regulatory T cells(Tregs).However,the role of m^(6)A methyltransferase in other subtypes of T cells remains unknown.T helper cells 17(Th17)play a pivotal role in host defense and autoimmunity.Here,we found that the loss of METTL3 in T cells caused serious defect of Th17 cell differentiation,and impeded the development of experimental autoimmune encephalomyelitis(EAE).We generated Mettl3f/fIl17aCre mice and observed that METTL3 deficiency in Th17 cells significantly suppressed the development of EAE and displayed less Th17 cell infiltration into central nervous system(CNS).Importantly,we demonstrated that depletion of METTL3 attenuated IL-17A and CCR5 expression by facilitating SOCS3 mRNA stability in Th17 cells,leading to disrupted Th17 cell differentiation and infiltration,and eventually attenuating the process of EAE.Collectively,our results highlight that m^(6)A modification sustains Th17 cell function,which provides new insights into the regulatory network of Th17 cells,and also implies a potential therapeutic target for Th17 cell mediated autoimmune disease.
基金supported by the National Natural Science Foundation of China (32171127 and 91949109)the HMU Marshal Initiative Funding (HMUMIF-21023, China)+3 种基金the Major Scientific Fund Project of Heilongjiang Province (ZD2019H001, China)the CAMS Innovation Fund for Medical Sciences (CIFMS, 2019-I2M5-078, China)the Guangdong Province Basic and Applied Basic Research Fund (2021A1515111049, China)Postgraduate Research and Practice Innovation Program of HMU (YJSCX202015HYD, China)
文摘Idiopathic pulmonary fibrosis(IPF)is a progressive disease with unknown etiology and limited therapeutic options.Activation of fibroblasts is a prominent feature of pulmonary fibrosis.Here we report that lncRNA DACH1(dachshund homolog 1)is downregulated in the lungs of IPF patients and in an experimental mouse model of lung fibrosis.LncDACH1 knockout mice develop spontaneous pulmonary fibrosis,whereas overexpression of LncDACH1 attenuated TGF-β1-induced aberrant activation,collagen deposition and differentiation of mouse lung fibroblasts.Similarly,forced expression of LncDACH1 not only prevented bleomycin(BLM)-induced lung fibrosis,but also reversed established lung fibrosis in a BLM model.Mechanistically,LncDACH1 binding to the serine/arginine-rich splicing factor 1(SRSF1)protein decreases its activity and inhibits the accumulation of Ctnnb1.Enhanced expression of SRSF1 blocked the anti-fibrotic effect of LncDACH1 in lung fibroblasts.Furthermore,loss of LncDACH1 promoted proliferation,differentiation,and extracellular matrix(ECM)deposition in mouse lung fibroblasts,whereas such effects were abolished by silencing of Ctnnb1.In addition,a conserved fragment of LncDACH1 alleviated hyperproliferation,ECM deposition and differentiation of MRC-5 cells driven by TGF-β1.Collectively,LncDACH1 inhibits lung fibrosis by interacting with SRSF1 to suppress CTNNB1 accumulation,suggesting that LncDACH1 might be a potential therapeutic target for pulmonary fibrosis.
基金supported by the National Natural Science Foundation of China(31830021,32030036,32000615,and 32100695)the National Key Research and Development Program of China(2020YFA0803502)+2 种基金the 111 Project(B16021)China Postdoctoral Science Foundation(2020M683180,2019M663374,and 2020T130251)Guangdong Basic and Applied Basic Research Foundation(2020A1515111045 and 2020A1515111081)。
