Background:Exposure to ethanol in utero leads to several brain development disorders including retinal abnormalities whose underlying cellular pathogenesis remains elusive.We have previously reported changes in electr...Background:Exposure to ethanol in utero leads to several brain development disorders including retinal abnormalities whose underlying cellular pathogenesis remains elusive.We have previously reported changes in electroretinogram recordings in moderate fetal alcohol exposure(MFAE)vervet monkeys.The goal of this study is to characterize the anatomical effects of moderate MFAE during the third trimester in the vervet monkey retina.Methods:Using immunohistochemistry and Western blots,we analyzed changes in the expression of cell-type specific proteins that may occur in the MFAE retina compared to the normal retina.We also compared the basic retinal anatomy across groups by examining retinal layering and thickness.Results:Our main result indicates that GFAP(a potent marker of astrocytes)immunoreactivity was increased in the MFAE retina indicating strong astrogliosis.There was no obvious change in the overall anatomy in the MFAE retina and no significant differences in the mean thickness of each retinal layer.Furthermore,no significant changes in the morphology of the photoreceptors,horizontal cells,bipolar cells,and amacrines cells was observed.Conclusions:These data indicate that astrogliosis is a consequence of prenatal alcohol exposure and might explain the reported changes in the electroretinographic responses.展开更多
Argatroban is a synthetic thrombin inhibitor approved by U.S.Food and Drug Administration for the treatment of thrombosis.However,whether it plays a role in the repair of spinal cord injury is unknown.In this study,we...Argatroban is a synthetic thrombin inhibitor approved by U.S.Food and Drug Administration for the treatment of thrombosis.However,whether it plays a role in the repair of spinal cord injury is unknown.In this study,we established a rat model of T10 moderate spinal cord injury using an NYU Impactor ModerⅢand performed intraperitoneal injection of argatroban for 3 consecutive days.Our results showed that argatroban effectively promoted neurological function recovery after spinal cord injury and decreased thrombin expression and activity in the local injured spinal cord.RNA sequencing transcriptomic analysis revealed that the differentially expressed genes in the argatroban-treated group were enriched in the JAK2/STAT3 pathway,which is involved in astrogliosis and glial scar formation.Western blotting and immunofluorescence results showed that argatroban downregulated the expression of the thrombin receptor PAR1 in the injured spinal cord and the JAK2/STAT3 signal pathway.Argatroban also inhibited the activation and proliferation of astrocytes and reduced glial scar formation in the spinal cord.Taken together,these findings suggest that argatroban may inhibit astrogliosis by inhibiting the thrombin-mediated PAR1/JAK2/STAT3 signal pathway,thereby promoting the recovery of neurological function after spinal cord injury.展开更多
Astrocytes are indispensable for central nervous system development and homeostasis.In response to injury and disease,astrocytes are integral to the immunological-and the,albeit limited,repair response.In this review,...Astrocytes are indispensable for central nervous system development and homeostasis.In response to injury and disease,astrocytes are integral to the immunological-and the,albeit limited,repair response.In this review,we will examine some of the functions reactive astrocytes play in the context of multiple sclerosis and related animal models.We will consider the heterogeneity or plasticity of astrocytes and the mechanisms by which they promote or mitigate demyelination.Finally,we will discuss a set of biomedical strategies that can stimulate astrocytes in their promyelinating response.展开更多
Ferroptosis is an iron-dependent novel cell death pathway. Deferoxamine, a ferroptosis inhibitor, has been reported to promote spinal cord injury repair. It has yet to be clarified whether ferroptosis inhibition repre...Ferroptosis is an iron-dependent novel cell death pathway. Deferoxamine, a ferroptosis inhibitor, has been reported to promote spinal cord injury repair. It has yet to be clarified whether ferroptosis inhibition represents the mechanism of action of Deferoxamine on spinal cord injury recovery. A rat model of Deferoxamine at thoracic 10 segment was established using a modified Allen's method. Ninety 8-week-old female Wistar rats were used. Rats in the Deferoxamine group were intraperitoneally injected with 100 mg/kg Deferoxamine 30 minutes before injury. Simultaneously, the Sham and Deferoxamine groups served as controls. Drug administration was conducted for 7 consecutive days. The results were as follows:(1) Electron microscopy revealed shrunken mitochondria in the spinal cord injury group.(2) The Basso, Beattie and Bresnahan locomotor rating score showed that recovery of the hindlimb was remarkably better in the Deferoxamine group than in the spinal cord injury group.(3) The iron concentration was lower in the Deferoxamine group than in the spinal cord injury group after injury.(4) Western blot assay revealed that, compared with the spinal cord injury group, GPX4, xCT, and glutathione expression was markedly increased in the Deferoxamine group.(5) Real-time polymerase chain reaction revealed that, compared with the Deferoxamine group, mRNA levels of ferroptosis-related genes Acyl-CoA synthetase family member 2(ACSF2) and iron-responsive element-binding protein 2(IREB2) were up-regulated in the Deferoxamine group.(6) Deferoxamine increased survival of neurons and inhibited gliosis. These findings confirm that Deferoxamine can repair spinal cord injury by inhibiting ferroptosis. Targeting ferroptosis is therefore a promising therapeutic approach for spinal cord injury.展开更多
Reactive astrogliosis occurs after central nervous system(CNS) injuries whereby resident astrocytes form rapid responses along a graded continuum. Following CNS lesions, na?ve astrocytes are converted into reactive as...Reactive astrogliosis occurs after central nervous system(CNS) injuries whereby resident astrocytes form rapid responses along a graded continuum. Following CNS lesions, na?ve astrocytes are converted into reactive astrocytes and eventually into scar-forming astrocytes that block axon regeneration and neural repair. It has been known for decades that scarring development and its related extracellular matrix molecules interfere with regeneration of injured axons after CNS injury, but the cellular and molecular mechanisms for controlling astrocytic scar formation and maintenance are not well known. Recent use of various genetic tools has made tremendous progress in better understanding genesis of reactive astrogliosis. Especially, the latest experiments demonstrate environment-dependent plasticity of reactive astrogliosis because reactive astrocytes isolated from injured spinal cord form scarring astrocytes when transplanted into injured spinal cord, but revert in retrograde to naive astrocytes when transplanted into naive spinal cord. The interactions between upregulated type I collagen and its receptor integrin β1 and the N-cadherin-mediated cell adhesion appear to play major roles for local astrogliosis around the lesion. This review centers on the environment-dependent plasticity of reactive astrogliosis after spinal cord injury and its potential as a therapeutic target.展开更多
Severe traumatic spinal cord injury(SCI)results in a devastating and permanent loss of function,and is currently an incurable condition.It is generally accepted that future intervention strategies will require combina...Severe traumatic spinal cord injury(SCI)results in a devastating and permanent loss of function,and is currently an incurable condition.It is generally accepted that future intervention strategies will require combinational approaches,including bioengineered scaffolds,to support axon growth across tissue scarring and cystic cavitation.Previously,we demonstrated that implantation of a microporous type-I collagen scaffold into an experimental model of SCI was capable of supporting functional recovery in the absence of extensive implant–host neural tissue integration.Here,we demonstrate the reactive host cellular responses that may be detrimental to neural tissue integration after implantation of collagen scaffolds into unilateral resection injuries of the adult rat spinal cord.Immunohistochemistry demonstrated scattered fibroblast-like cell infiltration throughout the scaffolds as well as the presence of variable layers of densely packed cells,the fine processes of which extended along the graft–host interface.Few reactive astroglial or regenerating axonal profiles could be seen traversing this layer.Such encapsulation-type behaviour around bioengineered scaffolds impedes the integration of host neural tissues and reduces the intended bridging role of the implant.Characterization of the cellular and molecular mechanisms underpinning this behaviour will be pivotal in the future design of collagen-based bridging scaffolds intended for regenerative medicine.展开更多
Previous studies have suggested that thrombospondin-1(TSP-1) regulates the transforming growth factor beta 1(TGF-b1)/phosphorylated Smad2/3(p Smad2/3) pathway. Moreover, TSP-1 is closely associated with epilepsy. Howe...Previous studies have suggested that thrombospondin-1(TSP-1) regulates the transforming growth factor beta 1(TGF-b1)/phosphorylated Smad2/3(p Smad2/3) pathway. Moreover, TSP-1 is closely associated with epilepsy. However, the role of the TSP-1-regulated TGFb1/p Smad2/3 pathway in seizures remains unclear. In this study, changes in this pathway were assessed following kainic acid(KA)-induced status epilepticus(SE) in rats.The results showed that increases in the TSP-1/TGF-b1/p Smad2/3 levels spatially and temporally matched the increases in glial fibrillary acidic protein(GFAP)/chondroitin sulfate(CS56) levels following KA administration.Inhibition of TSP-1 expression by small interfering RNA or inhibition of TGF-b1 activation with a Leu-Ser-Lys-Leu peptide significantly reduced the severity of KA-induced acute seizures. These anti-seizure effects were accompanied by decreased GFAP/CS56 expression and Smad2/3 phosphorylation. Moreover, inhibiting Smad2/3 phosphorylation with ponatinib or SIS3 also significantly reduced seizure severity, alongside reducing GFAP/CS56 immunoreactivity. These results suggest that the TSP-1-regulated TGF-b1/p Smad2/3 pathway plays a key role in KA-induced SE and astrogliosis, and that inhibiting this pathway may be a potential anti-seizure strategy.展开更多
The effect of ciliary neurotrophic factor (CNTF) on reactive astrogliosis was studied on a mechanical scratch model of the confluent astrocytic cultures from newborn rat brain. Following injury, the astrocytes at the ...The effect of ciliary neurotrophic factor (CNTF) on reactive astrogliosis was studied on a mechanical scratch model of the confluent astrocytic cultures from newborn rat brain. Following injury, the astrocytes at the edge of the injured area displayed a typical process of the reactive astrogliosis. This process included apparently hyperplastic change and significantly increased GFAP expression of the flat astrocytes, and migration to the injured area of the O-2A progenitor cells and their differentiation into process-bearing astrocytes. Exogenous CNTF applied to the cell cultures significantly promoted the hyperplasia and GFAP expression of the flat astrocytes. The results suggest that CNTF can enhance the reactive astrogliosis in the injured area.展开更多
Spinal cord injury(SCI)affects approximately 200,000 individuals per year worldwide.There are more than 27 million people worldwide living with long-term disability due to SCI.Historically,it was thought that the cent...Spinal cord injury(SCI)affects approximately 200,000 individuals per year worldwide.There are more than 27 million people worldwide living with long-term disability due to SCI.Historically,it was thought that the central nervous system(CNS)had little ability for regeneration;however,more recent studies have demonstrated potential for repair within the CNS.Because of this,there exists a renewed interest in the discovery of novel approaches to promote regeneration in the CNS including the spinal cord.It is important to know the roles of the microRNAs(miRNAs)in modulation of pathogenesis in SCI and the potentials of the miRNA-based clinical interventions for controlling post-injury symptoms and improving functional recovery.The miRNAs,which are non-coding RNAs with an average of 22 nucleotides in length,are post-transcriptional gene regulators that cause degradation of the target mRNAs and thus negatively control their translation.This review article focuses on current research related to miRNAs and their roles in modulating SCI symptoms,asserting that miRNAs contribute to critical post-SCI molecular processes including neuroplasticity,functional recovery,astrogliosis,neuropathic pain,inflammation,and apoptosis.In particular,miR-96 provides a promising therapeutic opportunity to improve the outcomes of clinical interventions,including the way SCI injuries are evaluated and treated.展开更多
文摘Background:Exposure to ethanol in utero leads to several brain development disorders including retinal abnormalities whose underlying cellular pathogenesis remains elusive.We have previously reported changes in electroretinogram recordings in moderate fetal alcohol exposure(MFAE)vervet monkeys.The goal of this study is to characterize the anatomical effects of moderate MFAE during the third trimester in the vervet monkey retina.Methods:Using immunohistochemistry and Western blots,we analyzed changes in the expression of cell-type specific proteins that may occur in the MFAE retina compared to the normal retina.We also compared the basic retinal anatomy across groups by examining retinal layering and thickness.Results:Our main result indicates that GFAP(a potent marker of astrocytes)immunoreactivity was increased in the MFAE retina indicating strong astrogliosis.There was no obvious change in the overall anatomy in the MFAE retina and no significant differences in the mean thickness of each retinal layer.Furthermore,no significant changes in the morphology of the photoreceptors,horizontal cells,bipolar cells,and amacrines cells was observed.Conclusions:These data indicate that astrogliosis is a consequence of prenatal alcohol exposure and might explain the reported changes in the electroretinographic responses.
基金supported by the Key Project of the National Natural Science Foundation of China,No.81930070(to SF)the National Natural Science Foundation of China,No.81972074(to XY)the Key Program of Natural Science Foundation of Tianjin,No.19JCZDJC34900(to XY)。
文摘Argatroban is a synthetic thrombin inhibitor approved by U.S.Food and Drug Administration for the treatment of thrombosis.However,whether it plays a role in the repair of spinal cord injury is unknown.In this study,we established a rat model of T10 moderate spinal cord injury using an NYU Impactor ModerⅢand performed intraperitoneal injection of argatroban for 3 consecutive days.Our results showed that argatroban effectively promoted neurological function recovery after spinal cord injury and decreased thrombin expression and activity in the local injured spinal cord.RNA sequencing transcriptomic analysis revealed that the differentially expressed genes in the argatroban-treated group were enriched in the JAK2/STAT3 pathway,which is involved in astrogliosis and glial scar formation.Western blotting and immunofluorescence results showed that argatroban downregulated the expression of the thrombin receptor PAR1 in the injured spinal cord and the JAK2/STAT3 signal pathway.Argatroban also inhibited the activation and proliferation of astrocytes and reduced glial scar formation in the spinal cord.Taken together,these findings suggest that argatroban may inhibit astrogliosis by inhibiting the thrombin-mediated PAR1/JAK2/STAT3 signal pathway,thereby promoting the recovery of neurological function after spinal cord injury.
基金supported by the Heart and Stroke Foundation and Ontario Institute of Regenerative Medicine (New Ideas Grant)Canada First Research Excellence Fund(Medicine by Design)+2 种基金the National Sciences and Engineering Research Councilthe Jurgen Manchot Foundationthe Christiane and Claudia Hempel Foundation for Clinical Stem Cell Research and the James and Elisabeth Cloppenburg,Peek and Cloppenburg Düsseldorf Stiftung (to PK)
文摘Astrocytes are indispensable for central nervous system development and homeostasis.In response to injury and disease,astrocytes are integral to the immunological-and the,albeit limited,repair response.In this review,we will examine some of the functions reactive astrocytes play in the context of multiple sclerosis and related animal models.We will consider the heterogeneity or plasticity of astrocytes and the mechanisms by which they promote or mitigate demyelination.Finally,we will discuss a set of biomedical strategies that can stimulate astrocytes in their promyelinating response.
基金supported by the National Natural Science Foundation of China,No.81672171(to XY),81330042(to SQF),81620108018(to SQF),81772342the State Key Laboratory of Medicinal Chemical Biology(Nankai University),China,No.2017027
文摘Ferroptosis is an iron-dependent novel cell death pathway. Deferoxamine, a ferroptosis inhibitor, has been reported to promote spinal cord injury repair. It has yet to be clarified whether ferroptosis inhibition represents the mechanism of action of Deferoxamine on spinal cord injury recovery. A rat model of Deferoxamine at thoracic 10 segment was established using a modified Allen's method. Ninety 8-week-old female Wistar rats were used. Rats in the Deferoxamine group were intraperitoneally injected with 100 mg/kg Deferoxamine 30 minutes before injury. Simultaneously, the Sham and Deferoxamine groups served as controls. Drug administration was conducted for 7 consecutive days. The results were as follows:(1) Electron microscopy revealed shrunken mitochondria in the spinal cord injury group.(2) The Basso, Beattie and Bresnahan locomotor rating score showed that recovery of the hindlimb was remarkably better in the Deferoxamine group than in the spinal cord injury group.(3) The iron concentration was lower in the Deferoxamine group than in the spinal cord injury group after injury.(4) Western blot assay revealed that, compared with the spinal cord injury group, GPX4, xCT, and glutathione expression was markedly increased in the Deferoxamine group.(5) Real-time polymerase chain reaction revealed that, compared with the Deferoxamine group, mRNA levels of ferroptosis-related genes Acyl-CoA synthetase family member 2(ACSF2) and iron-responsive element-binding protein 2(IREB2) were up-regulated in the Deferoxamine group.(6) Deferoxamine increased survival of neurons and inhibited gliosis. These findings confirm that Deferoxamine can repair spinal cord injury by inhibiting ferroptosis. Targeting ferroptosis is therefore a promising therapeutic approach for spinal cord injury.
基金supported by research grants to SL from NIH(1R01NS079432 and 1R01EY024575)Shriners Research Foundation(SHC-86300-PHI,SHC-86200-PHI-16 and SHC-85100)
文摘Reactive astrogliosis occurs after central nervous system(CNS) injuries whereby resident astrocytes form rapid responses along a graded continuum. Following CNS lesions, na?ve astrocytes are converted into reactive astrocytes and eventually into scar-forming astrocytes that block axon regeneration and neural repair. It has been known for decades that scarring development and its related extracellular matrix molecules interfere with regeneration of injured axons after CNS injury, but the cellular and molecular mechanisms for controlling astrocytic scar formation and maintenance are not well known. Recent use of various genetic tools has made tremendous progress in better understanding genesis of reactive astrogliosis. Especially, the latest experiments demonstrate environment-dependent plasticity of reactive astrogliosis because reactive astrocytes isolated from injured spinal cord form scarring astrocytes when transplanted into injured spinal cord, but revert in retrograde to naive astrocytes when transplanted into naive spinal cord. The interactions between upregulated type I collagen and its receptor integrin β1 and the N-cadherin-mediated cell adhesion appear to play major roles for local astrogliosis around the lesion. This review centers on the environment-dependent plasticity of reactive astrogliosis after spinal cord injury and its potential as a therapeutic target.
基金supported by the START-Program of the Faculty of Medicine,RWTH Aachen.
文摘Severe traumatic spinal cord injury(SCI)results in a devastating and permanent loss of function,and is currently an incurable condition.It is generally accepted that future intervention strategies will require combinational approaches,including bioengineered scaffolds,to support axon growth across tissue scarring and cystic cavitation.Previously,we demonstrated that implantation of a microporous type-I collagen scaffold into an experimental model of SCI was capable of supporting functional recovery in the absence of extensive implant–host neural tissue integration.Here,we demonstrate the reactive host cellular responses that may be detrimental to neural tissue integration after implantation of collagen scaffolds into unilateral resection injuries of the adult rat spinal cord.Immunohistochemistry demonstrated scattered fibroblast-like cell infiltration throughout the scaffolds as well as the presence of variable layers of densely packed cells,the fine processes of which extended along the graft–host interface.Few reactive astroglial or regenerating axonal profiles could be seen traversing this layer.Such encapsulation-type behaviour around bioengineered scaffolds impedes the integration of host neural tissues and reduces the intended bridging role of the implant.Characterization of the cellular and molecular mechanisms underpinning this behaviour will be pivotal in the future design of collagen-based bridging scaffolds intended for regenerative medicine.
基金the National Natural Science Foundation of China(81573412)the Key Research and Development Plan(2018GSF121004)the Natural Science Foundation of Shandong Province,China(ZR2014JL055).
文摘Previous studies have suggested that thrombospondin-1(TSP-1) regulates the transforming growth factor beta 1(TGF-b1)/phosphorylated Smad2/3(p Smad2/3) pathway. Moreover, TSP-1 is closely associated with epilepsy. However, the role of the TSP-1-regulated TGFb1/p Smad2/3 pathway in seizures remains unclear. In this study, changes in this pathway were assessed following kainic acid(KA)-induced status epilepticus(SE) in rats.The results showed that increases in the TSP-1/TGF-b1/p Smad2/3 levels spatially and temporally matched the increases in glial fibrillary acidic protein(GFAP)/chondroitin sulfate(CS56) levels following KA administration.Inhibition of TSP-1 expression by small interfering RNA or inhibition of TGF-b1 activation with a Leu-Ser-Lys-Leu peptide significantly reduced the severity of KA-induced acute seizures. These anti-seizure effects were accompanied by decreased GFAP/CS56 expression and Smad2/3 phosphorylation. Moreover, inhibiting Smad2/3 phosphorylation with ponatinib or SIS3 also significantly reduced seizure severity, alongside reducing GFAP/CS56 immunoreactivity. These results suggest that the TSP-1-regulated TGF-b1/p Smad2/3 pathway plays a key role in KA-induced SE and astrogliosis, and that inhibiting this pathway may be a potential anti-seizure strategy.
文摘The effect of ciliary neurotrophic factor (CNTF) on reactive astrogliosis was studied on a mechanical scratch model of the confluent astrocytic cultures from newborn rat brain. Following injury, the astrocytes at the edge of the injured area displayed a typical process of the reactive astrogliosis. This process included apparently hyperplastic change and significantly increased GFAP expression of the flat astrocytes, and migration to the injured area of the O-2A progenitor cells and their differentiation into process-bearing astrocytes. Exogenous CNTF applied to the cell cultures significantly promoted the hyperplasia and GFAP expression of the flat astrocytes. The results suggest that CNTF can enhance the reactive astrogliosis in the injured area.
基金The work was supported in part by an investigator-initiated research grant(SCIRF-2015-1-01)from South Carolina Spinal Cord Injury Research Fund(Columbia,SC,USA)an award from the Soy Health Research Program(SHRP,United Soybean Board,Chesterfield,MO,USA)and earlier R01 grants(CA-091460 and NS-057811)from the National Institutes of Health(Bethesda,MD,USA).
文摘Spinal cord injury(SCI)affects approximately 200,000 individuals per year worldwide.There are more than 27 million people worldwide living with long-term disability due to SCI.Historically,it was thought that the central nervous system(CNS)had little ability for regeneration;however,more recent studies have demonstrated potential for repair within the CNS.Because of this,there exists a renewed interest in the discovery of novel approaches to promote regeneration in the CNS including the spinal cord.It is important to know the roles of the microRNAs(miRNAs)in modulation of pathogenesis in SCI and the potentials of the miRNA-based clinical interventions for controlling post-injury symptoms and improving functional recovery.The miRNAs,which are non-coding RNAs with an average of 22 nucleotides in length,are post-transcriptional gene regulators that cause degradation of the target mRNAs and thus negatively control their translation.This review article focuses on current research related to miRNAs and their roles in modulating SCI symptoms,asserting that miRNAs contribute to critical post-SCI molecular processes including neuroplasticity,functional recovery,astrogliosis,neuropathic pain,inflammation,and apoptosis.In particular,miR-96 provides a promising therapeutic opportunity to improve the outcomes of clinical interventions,including the way SCI injuries are evaluated and treated.