In a recent work published in Neuron,Xu et al.identified a novel contribution of G protein-coupled receptor 37-like 1(GPR37L1),which is identified to be expressed by spinal astrocytes,to the regulation of neuropathic ...In a recent work published in Neuron,Xu et al.identified a novel contribution of G protein-coupled receptor 37-like 1(GPR37L1),which is identified to be expressed by spinal astrocytes,to the regulation of neuropathic pain[1].By interacting and enhancing the activity of glutamate transporter-1(GLT-1)in spinal astrocytes,GPR37L1 promotes glutamate uptake by spinal astrocytes and reduces excitatory synaptic transmission in the spinal dorsal horn,all of which contribute to the resolution of chronic neuropathic pain.展开更多
Irritable bowel syndrome is a gastrointestinal disorder of unknown etiology characterized by widespread,chronic abdominal pain associated with altered bowel movements.Increasing amounts of evidence indicate that injur...Irritable bowel syndrome is a gastrointestinal disorder of unknown etiology characterized by widespread,chronic abdominal pain associated with altered bowel movements.Increasing amounts of evidence indicate that injury and inflammation during the neonatal period have long-term effects on tissue structure and function in the adult that may predispose to gastrointestinal diseases.In this study we aimed to investigate how the epigenetic regulation of DNA demethylation of the p2x7r locus guided by the transcription factor GATA binding protein 1(GATA1)in spinal astrocytes affects chronic visceral pain in adult rats with neonatal colonic inflammation(NCI).The spinal GATA1 targeting to DNA demethylation of p2x7r locus in these rats was assessed by assessing GATA1 function with luciferase assay,chromatin immunoprecipitation,patch clamp,and interference in vitro and in vivo.In addition,a decoy oligodeoxynucleotide was designed and applied to determine the influence of GATA1 on the DNA methylation of a p2x7r CpG island.We showed that NCI caused the induction of GATA1,Ten-eleven translocation 3(TET3),and purinergic receptors(P2X7Rs)in astrocytes of the spinal dorsal horn,and demonstrated that inhibiting these molecules markedly increased the pain threshold,inhibited the activation of astrocytes,and decreased the spinal sEPSC frequency.NCI also markedly demethylated the p2x7r locus in a manner dependent on the enhancement of both a GATA1–TET3 physical interaction and GATA1 binding at the p2x7r promoter.Importantly,we showed that demethylation of the p2x7r locus(and the attendant increase in P2X7R expression)was reversed upon knockdown of GATA1 or TET3 expression,and demonstrated that a decoy oligodeoxynucleotide that selectively blocked the GATA1 binding site increased the methylation of a CpG island in the p2x7r promoter.These results demonstrate that chronic visceral pain is mediated synergistically by GATA1 and TET3 via a DNA-demethylation mechanism that controls p2x7r transcription in spinal dorsal horn astrocytes,and provide a potential therapeutic strategy by targeting GATA1 and p2x7r locus binding.展开更多
In the aftermath of spinal cord injury,glial restricted precursors（GRPs） and immature astrocytes offer the potential to modulate the inflammatory environment of the injured spinal cord and promote host axon regenera...In the aftermath of spinal cord injury,glial restricted precursors（GRPs） and immature astrocytes offer the potential to modulate the inflammatory environment of the injured spinal cord and promote host axon regeneration.Nevertheless clinical application of cellular therapy for the repair of spinal cord injury requires strict quality-assured protocols for large-scale production and preservation that necessitates long-term in vitro expansion.Importantly,such processes have the potential to alter the phenotypic and functional properties and thus therapeutic potential of these cells.Furthermore,clinical use of cellular therapies may be limited by the inflammatory microenvironment of the injured spinal cord,altering the phenotypic and functional properties of grafted cells.This report simulates the process of large-scale GRP production and demonstrates the permissive properties of GRP following long-term in vitro culture.Furthermore,we defined the phenotypic and functional properties of GRP in the presence of inflammatory factors,and call attention to the importance of the microenvironment of grafted cells,underscoring the importance of modulating the environment of the injured spinal cord.展开更多
基金supported by the National Natural Science Foundation of China(82474625)Zhejiang Provincial Natural Science Funds(LZ23H270001).
文摘In a recent work published in Neuron,Xu et al.identified a novel contribution of G protein-coupled receptor 37-like 1(GPR37L1),which is identified to be expressed by spinal astrocytes,to the regulation of neuropathic pain[1].By interacting and enhancing the activity of glutamate transporter-1(GLT-1)in spinal astrocytes,GPR37L1 promotes glutamate uptake by spinal astrocytes and reduces excitatory synaptic transmission in the spinal dorsal horn,all of which contribute to the resolution of chronic neuropathic pain.
基金supported by grants from National Natural Science Foundation of China(81801115,31730040,and 81920108016)the Priority Academic Program Development of Jiangsu Higher Education Institutions of China,and the China Postdoctoral Science Foundation(2018M642304).
文摘Irritable bowel syndrome is a gastrointestinal disorder of unknown etiology characterized by widespread,chronic abdominal pain associated with altered bowel movements.Increasing amounts of evidence indicate that injury and inflammation during the neonatal period have long-term effects on tissue structure and function in the adult that may predispose to gastrointestinal diseases.In this study we aimed to investigate how the epigenetic regulation of DNA demethylation of the p2x7r locus guided by the transcription factor GATA binding protein 1(GATA1)in spinal astrocytes affects chronic visceral pain in adult rats with neonatal colonic inflammation(NCI).The spinal GATA1 targeting to DNA demethylation of p2x7r locus in these rats was assessed by assessing GATA1 function with luciferase assay,chromatin immunoprecipitation,patch clamp,and interference in vitro and in vivo.In addition,a decoy oligodeoxynucleotide was designed and applied to determine the influence of GATA1 on the DNA methylation of a p2x7r CpG island.We showed that NCI caused the induction of GATA1,Ten-eleven translocation 3(TET3),and purinergic receptors(P2X7Rs)in astrocytes of the spinal dorsal horn,and demonstrated that inhibiting these molecules markedly increased the pain threshold,inhibited the activation of astrocytes,and decreased the spinal sEPSC frequency.NCI also markedly demethylated the p2x7r locus in a manner dependent on the enhancement of both a GATA1–TET3 physical interaction and GATA1 binding at the p2x7r promoter.Importantly,we showed that demethylation of the p2x7r locus(and the attendant increase in P2X7R expression)was reversed upon knockdown of GATA1 or TET3 expression,and demonstrated that a decoy oligodeoxynucleotide that selectively blocked the GATA1 binding site increased the methylation of a CpG island in the p2x7r promoter.These results demonstrate that chronic visceral pain is mediated synergistically by GATA1 and TET3 via a DNA-demethylation mechanism that controls p2x7r transcription in spinal dorsal horn astrocytes,and provide a potential therapeutic strategy by targeting GATA1 and p2x7r locus binding.
基金supported by NIH PO1 NS055976,CraigH.Neilsen Foundation
文摘In the aftermath of spinal cord injury,glial restricted precursors（GRPs） and immature astrocytes offer the potential to modulate the inflammatory environment of the injured spinal cord and promote host axon regeneration.Nevertheless clinical application of cellular therapy for the repair of spinal cord injury requires strict quality-assured protocols for large-scale production and preservation that necessitates long-term in vitro expansion.Importantly,such processes have the potential to alter the phenotypic and functional properties and thus therapeutic potential of these cells.Furthermore,clinical use of cellular therapies may be limited by the inflammatory microenvironment of the injured spinal cord,altering the phenotypic and functional properties of grafted cells.This report simulates the process of large-scale GRP production and demonstrates the permissive properties of GRP following long-term in vitro culture.Furthermore,we defined the phenotypic and functional properties of GRP in the presence of inflammatory factors,and call attention to the importance of the microenvironment of grafted cells,underscoring the importance of modulating the environment of the injured spinal cord.
