The impaired function of periodontal ligament stem cells(PDLSCs)impedes restoration of periodontal tissues.The cGAS-cGAMP-STING pathway is an innate immune pathway that sensing cytosolic double-stranded DNA(dsDNA),but...The impaired function of periodontal ligament stem cells(PDLSCs)impedes restoration of periodontal tissues.The cGAS-cGAMP-STING pathway is an innate immune pathway that sensing cytosolic double-stranded DNA(dsDNA),but its role in regulating the function of PDLSCs is still unclear.In this study,we found that mito-chondrial DNA(mtDNA)was released into the cytoplasm through the mitochondrial permeability transition pore(mPTP)in PDLSCs upon inflammation,which binds to cGAS and activated the STING pathway by promoting the production of cGAMP,and ultimately impaired the osteogenic differentiation of PDLSCs.Additionally,it is first found that inflammation can down-regulate the level of the ATP-binding cassette membrane subfamily member C1(ABCC1,a cGAMP exocellular transporter)and ectonucleotide pyrophosphatase/phosphodiesterase 1(ENPP1,a cGAMP hydrolase),which further aggravated the accumulation of intracellular cGAMP,leading to the persistent activation of the cGAS-STING pathway and thus the impaired the differentiation capacity of PDLSCs.Furthermore,we designed a hydrogel system loaded with a mPTP blocker,an ABCC1 agonist and ENPP1 to promote periodontal tissue regeneration by modulating the production,exocytosis,and clearance of cGAMP.In conclusion,our results highlight the profound effects,and specific mechanisms,of the cGAS-STING pathway on the function of stem cells and propose a new strategy to promote periodontal tissue restoration based on the reestablishment of cGAMP homeostasis.展开更多
Background:The study of autoinflammatory diseases has uncovered mechanisms underlying cytokine dysregulation and inflammation.Methods:We analyzed the DNA of an index patient with early-onset systemic inflammation,cuta...Background:The study of autoinflammatory diseases has uncovered mechanisms underlying cytokine dysregulation and inflammation.Methods:We analyzed the DNA of an index patient with early-onset systemic inflammation,cutaneous vasculopathy,and pulmonary inflammation.We sequenced a candidate gene,TMEM173,encoding the stimulator of interferon genes(STING),in this patient and in five unrelated children with similar clinical phenotypes.Four children were evaluated clinically and immunologically.With the STING ligand cyclic guanosine monophosphate-adenosine monophosphate(cGAMP),we stimulated peripheral-blood mononuclear cells and fibroblasts from patients and controls,as well as commercially obtained endothelial cells,and then assayed transcription of IFNB1,the gene encoding interferon-β,in the stimulated cells.We analyzed IFNB1 reporter levels in HEK293T cells cotransfected with mutant or nonmutant STING constructs.Mutant STING leads to increased phosphorylation of signal transducer and activator of transcription 1(STAT1),so we tested the effect of Janus kinase(JAK)inhibitors on STAT1 phosphorylation in lymphocytes from the affected children and controls.展开更多
基金the National Natural Science Founda-tion of China(82220108019 to P.Ji and 82201059 to Q.M.Zhai)the Chongqing Postdoctoral Science Special Foundation(2021XM1031 to Q.M.Zhai)+1 种基金China Postdoctoral Science Foundation(2022M720599 to Q.M.Zhai)Haobo medical technology(Shanghai)limited company helped us synthesize the PEGA materials.
文摘The impaired function of periodontal ligament stem cells(PDLSCs)impedes restoration of periodontal tissues.The cGAS-cGAMP-STING pathway is an innate immune pathway that sensing cytosolic double-stranded DNA(dsDNA),but its role in regulating the function of PDLSCs is still unclear.In this study,we found that mito-chondrial DNA(mtDNA)was released into the cytoplasm through the mitochondrial permeability transition pore(mPTP)in PDLSCs upon inflammation,which binds to cGAS and activated the STING pathway by promoting the production of cGAMP,and ultimately impaired the osteogenic differentiation of PDLSCs.Additionally,it is first found that inflammation can down-regulate the level of the ATP-binding cassette membrane subfamily member C1(ABCC1,a cGAMP exocellular transporter)and ectonucleotide pyrophosphatase/phosphodiesterase 1(ENPP1,a cGAMP hydrolase),which further aggravated the accumulation of intracellular cGAMP,leading to the persistent activation of the cGAS-STING pathway and thus the impaired the differentiation capacity of PDLSCs.Furthermore,we designed a hydrogel system loaded with a mPTP blocker,an ABCC1 agonist and ENPP1 to promote periodontal tissue regeneration by modulating the production,exocytosis,and clearance of cGAMP.In conclusion,our results highlight the profound effects,and specific mechanisms,of the cGAS-STING pathway on the function of stem cells and propose a new strategy to promote periodontal tissue restoration based on the reestablishment of cGAMP homeostasis.
文摘Background:The study of autoinflammatory diseases has uncovered mechanisms underlying cytokine dysregulation and inflammation.Methods:We analyzed the DNA of an index patient with early-onset systemic inflammation,cutaneous vasculopathy,and pulmonary inflammation.We sequenced a candidate gene,TMEM173,encoding the stimulator of interferon genes(STING),in this patient and in five unrelated children with similar clinical phenotypes.Four children were evaluated clinically and immunologically.With the STING ligand cyclic guanosine monophosphate-adenosine monophosphate(cGAMP),we stimulated peripheral-blood mononuclear cells and fibroblasts from patients and controls,as well as commercially obtained endothelial cells,and then assayed transcription of IFNB1,the gene encoding interferon-β,in the stimulated cells.We analyzed IFNB1 reporter levels in HEK293T cells cotransfected with mutant or nonmutant STING constructs.Mutant STING leads to increased phosphorylation of signal transducer and activator of transcription 1(STAT1),so we tested the effect of Janus kinase(JAK)inhibitors on STAT1 phosphorylation in lymphocytes from the affected children and controls.
