Axonal remodeling is a critical aspect of ischemic brain repair processes and contributes to spontaneous functional recovery.Our previous in vitro study demonstrated that exosomes/small extracellular vesicles(sEVs)iso...Axonal remodeling is a critical aspect of ischemic brain repair processes and contributes to spontaneous functional recovery.Our previous in vitro study demonstrated that exosomes/small extracellular vesicles(sEVs)isolated from cerebral endothelial cells(CEC-sEVs)of ischemic brain promote axonal growth of embryonic cortical neurons and that microRNA 27a(miR-27a)is an elevated miRNA in ischemic CEC-sEVs.In the present study,we investigated whether normal CEC-sEVs engineered to enrich their levels of miR-27a(27a-sEVs)further enhance axonal growth and improve neurological outcomes after ischemic stroke when compared with treatment with non-engineered CEC-sEVs.27a-sEVs were isolated from the conditioned medium of healthy mouse CECs transfected with a lentiviral miR-27a expression vector.Small EVs isolated from CECs transfected with a scramble vector(Scra-sEVs)were used as a control.Adult male mice were subjected to permanent middle cerebral artery occlusion and then were randomly treated with 27a-sEVs or Scra-sEVs.An array of behavior assays was used to measure neurological function.Compared with treatment of ischemic stroke with Scra-sEVs,treatment with 27a-sEVs significantly augmented axons and spines in the peri-infarct zone and in the corticospinal tract of the spinal grey matter of the denervated side,and significantly improved neurological outcomes.In vitro studies demonstrated that CEC-sEVs carrying reduced miR-27a abolished 27a-sEV-augmented axonal growth.Ultrastructural analysis revealed that 27a-sEVs systemically administered preferentially localized to the pre-synaptic active zone,while quantitative reverse transcription-polymerase chain reaction and Western Blot analysis showed elevated miR-27a,and reduced axonal inhibitory proteins Semaphorin 6A and Ras Homolog Family Member A in the peri-infarct zone.Blockage of the Clathrin-dependent endocytosis pathway substantially reduced neuronal internalization of 27a-sEVs.Our data provide evidence that 27a-sEVs have a therapeutic effect on stroke recovery by promoting axonal remodeling and improving neurological outcomes.Our findings also suggest that suppression of axonal inhibitory proteins such as Semaphorin 6A may contribute to the beneficial effect of 27a-sEVs on axonal remodeling.展开更多
INTRODUCTIONHepatitis G virus(HGV),also known as GB virus C,is arecently cloned virus which may be associated with humannon A-E hepatitis.It is parenterally transmitted andusually coinfected or superinfected with hepa...INTRODUCTIONHepatitis G virus(HGV),also known as GB virus C,is arecently cloned virus which may be associated with humannon A-E hepatitis.It is parenterally transmitted andusually coinfected or superinfected with hepatitis B orhepatitis C virus.Some investigations have展开更多
Diabetes mellitus affects an estimated 422 million people worldwide.Peripheral neuropathy is one of the most common and disabling complications of diabetes.There is currently no effective treatment for diabetic neurop...Diabetes mellitus affects an estimated 422 million people worldwide.Peripheral neuropathy is one of the most common and disabling complications of diabetes.There is currently no effective treatment for diabetic neuropathy,even with diligent blood展开更多
Traumatic brain injury(TBI):Despite improved supportive and rehabilitative care of TBI patients,TBI remains a leading cause of death and disability worldwide.To date,no effective pharmacological treatments are availab...Traumatic brain injury(TBI):Despite improved supportive and rehabilitative care of TBI patients,TBI remains a leading cause of death and disability worldwide.To date,no effective pharmacological treatments are available for TBI.The mechanisms underlying brain damage and repair following TBI are complex and not completely understood.Coagulopathy after TBI is frequent and an independent prognostic factor for unfavorable outcome and prognosis(Stein and Smith,2004).It may be amenable to treatment,and effective management of coagulopathy may protect from secondary injury and poor outcomes.Although the展开更多
基金supported by the NIH grants,R01 NS111801(to ZGZ)American Heart Association 16SDG29860003(to YZ)。
文摘Axonal remodeling is a critical aspect of ischemic brain repair processes and contributes to spontaneous functional recovery.Our previous in vitro study demonstrated that exosomes/small extracellular vesicles(sEVs)isolated from cerebral endothelial cells(CEC-sEVs)of ischemic brain promote axonal growth of embryonic cortical neurons and that microRNA 27a(miR-27a)is an elevated miRNA in ischemic CEC-sEVs.In the present study,we investigated whether normal CEC-sEVs engineered to enrich their levels of miR-27a(27a-sEVs)further enhance axonal growth and improve neurological outcomes after ischemic stroke when compared with treatment with non-engineered CEC-sEVs.27a-sEVs were isolated from the conditioned medium of healthy mouse CECs transfected with a lentiviral miR-27a expression vector.Small EVs isolated from CECs transfected with a scramble vector(Scra-sEVs)were used as a control.Adult male mice were subjected to permanent middle cerebral artery occlusion and then were randomly treated with 27a-sEVs or Scra-sEVs.An array of behavior assays was used to measure neurological function.Compared with treatment of ischemic stroke with Scra-sEVs,treatment with 27a-sEVs significantly augmented axons and spines in the peri-infarct zone and in the corticospinal tract of the spinal grey matter of the denervated side,and significantly improved neurological outcomes.In vitro studies demonstrated that CEC-sEVs carrying reduced miR-27a abolished 27a-sEV-augmented axonal growth.Ultrastructural analysis revealed that 27a-sEVs systemically administered preferentially localized to the pre-synaptic active zone,while quantitative reverse transcription-polymerase chain reaction and Western Blot analysis showed elevated miR-27a,and reduced axonal inhibitory proteins Semaphorin 6A and Ras Homolog Family Member A in the peri-infarct zone.Blockage of the Clathrin-dependent endocytosis pathway substantially reduced neuronal internalization of 27a-sEVs.Our data provide evidence that 27a-sEVs have a therapeutic effect on stroke recovery by promoting axonal remodeling and improving neurological outcomes.Our findings also suggest that suppression of axonal inhibitory proteins such as Semaphorin 6A may contribute to the beneficial effect of 27a-sEVs on axonal remodeling.
基金a grant from the National 863 Plans,№102-07-02-07
文摘INTRODUCTIONHepatitis G virus(HGV),also known as GB virus C,is arecently cloned virus which may be associated with humannon A-E hepatitis.It is parenterally transmitted andusually coinfected or superinfected with hepatitis B orhepatitis C virus.Some investigations have
基金supported by NINDS grants RO1 NS075084(LW)NIDDK RO1 DK097519(LW)
文摘Diabetes mellitus affects an estimated 422 million people worldwide.Peripheral neuropathy is one of the most common and disabling complications of diabetes.There is currently no effective treatment for diabetic neuropathy,even with diligent blood
文摘Traumatic brain injury(TBI):Despite improved supportive and rehabilitative care of TBI patients,TBI remains a leading cause of death and disability worldwide.To date,no effective pharmacological treatments are available for TBI.The mechanisms underlying brain damage and repair following TBI are complex and not completely understood.Coagulopathy after TBI is frequent and an independent prognostic factor for unfavorable outcome and prognosis(Stein and Smith,2004).It may be amenable to treatment,and effective management of coagulopathy may protect from secondary injury and poor outcomes.Although the
