Attempts have been made to use cell transplantation and biomaterials to promote cell proliferation,differentiation,migration,and survival,as well as angiogenesis,in the context of brain injury.However,whether bioactiv...Attempts have been made to use cell transplantation and biomaterials to promote cell proliferation,differentiation,migration,and survival,as well as angiogenesis,in the context of brain injury.However,whether bioactive materials can repair the damage caused by ischemic stroke by activating endogenous neurogenesis and angiogenesis is still unknown.In this study,we applied chitosan gel loaded with basic fibroblast growth factor to the stroke cavity 7 days after ischemic stroke in rats.The gel slowly released basic fibroblast growth factor,which improved the local microenvironment,activated endogenous neural stem/progenitor cells,and recruited these cells to migrate toward the penumbra and stroke cavity and subsequently differentiate into neurons,while enhancing angiogenesis in the penumbra and stroke cavity and ultimately leading to partial functional recovery.This study revealed the mechanism by which bioactive materials repair ischemic strokes,thus providing a new strategy for the clinical application of bioactive materials in the treatment of ischemic stroke.展开更多
Stroke can cause Wallerian degeneration in regions outside of the brain,particularly in the corticospinal tract.To investigate the fate of major glial cells and axons within affected areas of the corticospinal tract f...Stroke can cause Wallerian degeneration in regions outside of the brain,particularly in the corticospinal tract.To investigate the fate of major glial cells and axons within affected areas of the corticospinal tract following stroke,we induced photochemical infarction of the sensorimotor cortex leading to Wallerian degeneration along the full extent of the corticospinal tract.We first used a routine,sensitive marker of axonal injury,amyloid precursor protein,to examine Wallerian degeneration of the corticospinal tract.An antibody to amyloid precursor protein mapped exclusively to proximal axonal segments within the ischemic cortex,with no positive signal in distal parts of the corticospinal tract,at all time points.To improve visualization of Wallerian degeneration,we next utilized an orthograde virus that expresses green fluorescent protein to label the corticospinal tract and then quantitatively evaluated green fluorescent protein-expressing axons.Using this approach,we found that axonal degeneration began on day 3 post-stroke and was almost complete by 7 days after stroke.In addition,microglia mobilized and activated early,from day 7 after stroke,but did not maintain a phagocytic state over time.Meanwhile,astrocytes showed relatively delayed mobilization and a moderate response to Wallerian degeneration.Moreover,no anterograde degeneration of spinal anterior horn cells was observed in response to Wallerian degeneration of the corticospinal tract.In conclusion,our data provide evidence for dynamic,pathogenic spatiotemporal changes in major cellular components of the corticospinal tract during Wallerian degeneration.展开更多
Neurotrophic keratopathy is a persistent defect of the corneal epithelium,with or without stromal ulceration,due to corneal nerve deficiency caused by a variety of etiologies.The treatment options for neurotrophic ker...Neurotrophic keratopathy is a persistent defect of the corneal epithelium,with or without stromal ulceration,due to corneal nerve deficiency caused by a variety of etiologies.The treatment options for neurotrophic keratopathy are limited.In this study,an ophthalmic solution was constructed from a chitosan-based thermosensitive hydrogel with long-term release of murine nerve growth factor(CTH-mNGF).Its effectiveness was evaluated in corneal denervation(CD)mice and patients with neurotrophic keratopathy.In the preclinical setting,CTH-mNGF was assessed in a murine corneal denervation model.CTH-mNGF was transparent,thermosensitive,and ensured sustained release of mNGF for over 20 hours on the ocular surface,maintaining the local mNGF concentration around 1300 pg/mL in vivo.Corneal denervation mice treated with CTH-mNGF for 10 days showed a significant increase in corneal nerve area and total corneal nerve length compared with non-treated and CTH treated mice.A subsequent clinical trial of CTH-mNGF was conducted in patients with stage 2 or 3 neurotrophic keratopathy.Patients received topical CTH-mNGF twice daily for 8 weeks.Fluorescein sodium images,Schirmer’s test,intraocular pressure,Cochet-Bonnet corneal perception test,and best corrected visual acuity were evaluated.In total,six patients(total of seven eyes)diagnosed with neurotrophic keratopathy were enrolled.After 8 weeks of CTH-mNGF treatment,all participants showed a decreased area of corneal epithelial defect,as stained by fluorescence.Overall,six out of seven eyes had fluorescence staining scores<5.Moreover,best corrected visual acuity,intraocular pressure,Schirmer’s test and Cochet-Bonnet corneal perception test results showed no significant improvement.An increase in corneal nerve density was observed by in vivo confocal microscopy after 8 weeks of CTH-mNGF treatment in three out of seven eyes.This study demonstrates that CTH-mNGF is transparent,thermosensitive,and has sustained-release properties.Its effectiveness in healing corneal epithelial defects in all eyes with neurotrophic keratopathy suggests CTH-mNGF has promising application prospects in the treatment of neurotrophic keratopathy,being convenient and cost effective.展开更多
Adult endogenous neurogenesis was first defined as the generation of neurons and glia cells in the central nervous system(CNS);it was subsequently referred to as the activation of endogenous neural stem cells,and ulti...Adult endogenous neurogenesis was first defined as the generation of neurons and glia cells in the central nervous system(CNS);it was subsequently referred to as the activation of endogenous neural stem cells,and ultimately limited to the generation of new neurons[1].The research team led by Xiaoguang Li enriched this concept in 2015:Endogenous neural stem cells in the adult CNS can be activated,recruited,and migrated to the injured area,where these stem cells further differentiate into mature neurons.展开更多
During the whole life cycle of mammals,new neurons are constantly regenerated in the subgranular zone of the dentate gyrus and in the subventricular zone of the lateral ventricles.Thanks to emerging methodologies,grea...During the whole life cycle of mammals,new neurons are constantly regenerated in the subgranular zone of the dentate gyrus and in the subventricular zone of the lateral ventricles.Thanks to emerging methodologies,great progress has been made in the characterization of spinal cord endogenous neural stem cells(ependymal cells) and identification of their role in adult spinal cord development.As recently evidenced,both the intrinsic and extrinsic molecular mechanisms of ependymal cells control the sequential steps of the adult spinal cord neurogenesis.This review introduces the concept of adult endogenous neurogenesis,the reaction of ependymal cells after adult spinal cord injury(SCI),the heterogeneity and markers of ependymal cells,the factors that regulate ependymal cells,and the niches that impact the activation or differentiation of ependymal cells.展开更多
The present study aimed to explore the potential of the sodium hyaluronate-CNTF (ciliary neurotrophic factor) scaffold in activating endogenous neurogenesis and facilitating neural network re-formation after the adult...The present study aimed to explore the potential of the sodium hyaluronate-CNTF (ciliary neurotrophic factor) scaffold in activating endogenous neurogenesis and facilitating neural network re-formation after the adult rat spinal cord injury (SCI). After completely cutting and removing a 5-mm adult rat T8 segment, a sodium hyaluronate-CNTF scaffold was implanted into the lesion area. Dil tracing and immunofluorescence staining were used to observe the proliferation, differentiation and integration of neural stem cells (NSCs) after SCI. A planar multielectrode dish system (MED64) was used to test the electrophysiological characteristics of the regenerated neural network in the lesioned area. Electrophysiology and behavior evaluation were used to evaluate functional recovery of paraplegic rat hindlimbs. The Dil tracing and immunofluorescence results suggest that the sodium hyaluronate-CNTF scaffold could activate the NSCs originating from the spinal cord ependymal, and facilitate their migration to the lesion area and differentiation into mature neurons, which were capable of forming synaptic contact and receiving glutamatergic excitatory synaptic input. The MED64 results suggest that functional synapsis could be established among regenerated neurons as well as between regenerated neurons and the host tissue, which has been evidenced to be glutamatergic excitatory synapsis. The electrophysiology and behavior evaluation results indicate that the paraplegic rats’ sensory and motor functions were recovered in some degree. Collectively, this study may shed light on paraplegia treatment in clinics.展开更多
Spinal cord injury(SCI)is a severe damage usually leading to limb dysesthesia,motor dysfunction,and other physiological disability.We have previously shown that NT3-chitosan could trigger an acute SCI repairment in ra...Spinal cord injury(SCI)is a severe damage usually leading to limb dysesthesia,motor dysfunction,and other physiological disability.We have previously shown that NT3-chitosan could trigger an acute SCI repairment in rats and non-human primates.Due to the negative effect of inhibitory molecules in glial scar on axonal regeneration,however,the role of NT3-chitosan in the treatment of chronic SCI remains unclear.Compared with the fresh wound of acute SCI,how to handle the lesion core and glial scars is a major issue related to chronic-SCI repair.Here we report,in a chronic complete SCI rat model,establishment of magnetic resonancediffusion tensor imaging(MR-DTI)methods to monitor spatial and temporal changes of the lesion area,which matched well with anatomical analyses.Clearance of the lesion core via suction of cystic tissues and trimming of solid scar tissues before introducing NT3-chitosan using either a rigid tubular scaffold or a soft gel form led to robust neural regeneration,which interconnected the severed ascending and descending axons and accompanied with electrophysiological and motor functional recovery.In contrast,cystic tissue extraction without scar trimming followed by NT3-chitosan injection,resulted in little,if any regeneration.Taken together,after lesion core clearance,NT3-chitosan can be used to enable chronic-SCI repair and MR-DTI-based mapping of lesion area and monitoring of ongoing regeneration can potentially be implemented in clinical studies for subacute/chronic-SCI repair.展开更多
Different types of traumatic brain injury(TBI)have posed a hazard to human health for a while,and their aftereffects have a significant negative impact on patients'quality of life.Despite the increased attention t...Different types of traumatic brain injury(TBI)have posed a hazard to human health for a while,and their aftereffects have a significant negative impact on patients'quality of life.Despite the increased attention that TBI has received recently,the clinical treatment plan that is currently in place only consists of palliative therapy for neuroprotection or the mitigation of secondary injury,which has only a minimally positive impact on the prognosis and quality of life in TBI patients.After TBI,regenerative therapy seeks to improve the patient's function.Cell therapy,which has become one of the hottest research fields,is expected to improve the therapeutic effect of this disease.This article will briefly discuss recent developments in research of TBI and available treatments,and then give a general assessment of the outlook.展开更多
基金supported by the National Natural Science Foundation of China,Nos.81941011(to XL),31771053(to HD),31730030(to XL),31971279(to ZY),31900749(to PH),31650001(to XL),31320103903(to XL),31670988(to ZY)the Natural Science Foundation of Beijing,Nos.7222004(to HD)+1 种基金a grant from Ministry of Science and Technology of China,Nos.2017YFC1104002(to ZY),2017YFC1104001(to XL)a grant from Beihang University,No.JKF-YG-22-B001(to FH)。
文摘Attempts have been made to use cell transplantation and biomaterials to promote cell proliferation,differentiation,migration,and survival,as well as angiogenesis,in the context of brain injury.However,whether bioactive materials can repair the damage caused by ischemic stroke by activating endogenous neurogenesis and angiogenesis is still unknown.In this study,we applied chitosan gel loaded with basic fibroblast growth factor to the stroke cavity 7 days after ischemic stroke in rats.The gel slowly released basic fibroblast growth factor,which improved the local microenvironment,activated endogenous neural stem/progenitor cells,and recruited these cells to migrate toward the penumbra and stroke cavity and subsequently differentiate into neurons,while enhancing angiogenesis in the penumbra and stroke cavity and ultimately leading to partial functional recovery.This study revealed the mechanism by which bioactive materials repair ischemic strokes,thus providing a new strategy for the clinical application of bioactive materials in the treatment of ischemic stroke.
基金supported by the National Natural Science Foundation of China,Nos.31 730030 (to XL),81941011 (to XL),31 771053 (to HD),82271403 (to XL),82272171 (to ZY),31971279 (to ZY)82201542 (to FH)+1 种基金the Natural Science Foundation of Beijing,No.7222004 (to HD)the Science and Technology Program of Beijing,No.Z181100001818007(to ZY)
文摘Stroke can cause Wallerian degeneration in regions outside of the brain,particularly in the corticospinal tract.To investigate the fate of major glial cells and axons within affected areas of the corticospinal tract following stroke,we induced photochemical infarction of the sensorimotor cortex leading to Wallerian degeneration along the full extent of the corticospinal tract.We first used a routine,sensitive marker of axonal injury,amyloid precursor protein,to examine Wallerian degeneration of the corticospinal tract.An antibody to amyloid precursor protein mapped exclusively to proximal axonal segments within the ischemic cortex,with no positive signal in distal parts of the corticospinal tract,at all time points.To improve visualization of Wallerian degeneration,we next utilized an orthograde virus that expresses green fluorescent protein to label the corticospinal tract and then quantitatively evaluated green fluorescent protein-expressing axons.Using this approach,we found that axonal degeneration began on day 3 post-stroke and was almost complete by 7 days after stroke.In addition,microglia mobilized and activated early,from day 7 after stroke,but did not maintain a phagocytic state over time.Meanwhile,astrocytes showed relatively delayed mobilization and a moderate response to Wallerian degeneration.Moreover,no anterograde degeneration of spinal anterior horn cells was observed in response to Wallerian degeneration of the corticospinal tract.In conclusion,our data provide evidence for dynamic,pathogenic spatiotemporal changes in major cellular components of the corticospinal tract during Wallerian degeneration.
基金supported by PLA General Hospital Program,No.LB20201A010024(to LW).
文摘Neurotrophic keratopathy is a persistent defect of the corneal epithelium,with or without stromal ulceration,due to corneal nerve deficiency caused by a variety of etiologies.The treatment options for neurotrophic keratopathy are limited.In this study,an ophthalmic solution was constructed from a chitosan-based thermosensitive hydrogel with long-term release of murine nerve growth factor(CTH-mNGF).Its effectiveness was evaluated in corneal denervation(CD)mice and patients with neurotrophic keratopathy.In the preclinical setting,CTH-mNGF was assessed in a murine corneal denervation model.CTH-mNGF was transparent,thermosensitive,and ensured sustained release of mNGF for over 20 hours on the ocular surface,maintaining the local mNGF concentration around 1300 pg/mL in vivo.Corneal denervation mice treated with CTH-mNGF for 10 days showed a significant increase in corneal nerve area and total corneal nerve length compared with non-treated and CTH treated mice.A subsequent clinical trial of CTH-mNGF was conducted in patients with stage 2 or 3 neurotrophic keratopathy.Patients received topical CTH-mNGF twice daily for 8 weeks.Fluorescein sodium images,Schirmer’s test,intraocular pressure,Cochet-Bonnet corneal perception test,and best corrected visual acuity were evaluated.In total,six patients(total of seven eyes)diagnosed with neurotrophic keratopathy were enrolled.After 8 weeks of CTH-mNGF treatment,all participants showed a decreased area of corneal epithelial defect,as stained by fluorescence.Overall,six out of seven eyes had fluorescence staining scores<5.Moreover,best corrected visual acuity,intraocular pressure,Schirmer’s test and Cochet-Bonnet corneal perception test results showed no significant improvement.An increase in corneal nerve density was observed by in vivo confocal microscopy after 8 weeks of CTH-mNGF treatment in three out of seven eyes.This study demonstrates that CTH-mNGF is transparent,thermosensitive,and has sustained-release properties.Its effectiveness in healing corneal epithelial defects in all eyes with neurotrophic keratopathy suggests CTH-mNGF has promising application prospects in the treatment of neurotrophic keratopathy,being convenient and cost effective.
文摘Adult endogenous neurogenesis was first defined as the generation of neurons and glia cells in the central nervous system(CNS);it was subsequently referred to as the activation of endogenous neural stem cells,and ultimately limited to the generation of new neurons[1].The research team led by Xiaoguang Li enriched this concept in 2015:Endogenous neural stem cells in the adult CNS can be activated,recruited,and migrated to the injured area,where these stem cells further differentiate into mature neurons.
基金supported by the State Key Program of National Natural Science Foundation of China(31130022,31320103903,31271037)the National Science and Technology Pillar Program of China(2012BAI17B04)+2 种基金the International Cooperation in Science and Technology Projects of the Ministry of Science Technology of China(2014DFA30640)the National Ministry of Education Special Fund for Excellent Doctoral Dissertation(201356)the Special Funds for Excellent Doctoral Dissertation of Beijing,China(20111000601)
文摘During the whole life cycle of mammals,new neurons are constantly regenerated in the subgranular zone of the dentate gyrus and in the subventricular zone of the lateral ventricles.Thanks to emerging methodologies,great progress has been made in the characterization of spinal cord endogenous neural stem cells(ependymal cells) and identification of their role in adult spinal cord development.As recently evidenced,both the intrinsic and extrinsic molecular mechanisms of ependymal cells control the sequential steps of the adult spinal cord neurogenesis.This review introduces the concept of adult endogenous neurogenesis,the reaction of ependymal cells after adult spinal cord injury(SCI),the heterogeneity and markers of ependymal cells,the factors that regulate ependymal cells,and the niches that impact the activation or differentiation of ependymal cells.
基金supported by the State Key Program of the National Natural Science Foundation of China (31130022,31320103903, 31271037 & 31670988)the International Cooperation in Science and Technology Project of the Ministry of Science and Technology of China (2014DFA30640)+2 种基金the National Ministry of Education Special Fund for Excellent Doctoral Dissertation (201356)the Special Fund for Excellent Doctoral Dissertation of Beijing (20111000601)the Special Funds for Beijing Base Construction & Talent Cultivation (171100002217066)
文摘The present study aimed to explore the potential of the sodium hyaluronate-CNTF (ciliary neurotrophic factor) scaffold in activating endogenous neurogenesis and facilitating neural network re-formation after the adult rat spinal cord injury (SCI). After completely cutting and removing a 5-mm adult rat T8 segment, a sodium hyaluronate-CNTF scaffold was implanted into the lesion area. Dil tracing and immunofluorescence staining were used to observe the proliferation, differentiation and integration of neural stem cells (NSCs) after SCI. A planar multielectrode dish system (MED64) was used to test the electrophysiological characteristics of the regenerated neural network in the lesioned area. Electrophysiology and behavior evaluation were used to evaluate functional recovery of paraplegic rat hindlimbs. The Dil tracing and immunofluorescence results suggest that the sodium hyaluronate-CNTF scaffold could activate the NSCs originating from the spinal cord ependymal, and facilitate their migration to the lesion area and differentiation into mature neurons, which were capable of forming synaptic contact and receiving glutamatergic excitatory synaptic input. The MED64 results suggest that functional synapsis could be established among regenerated neurons as well as between regenerated neurons and the host tissue, which has been evidenced to be glutamatergic excitatory synapsis. The electrophysiology and behavior evaluation results indicate that the paraplegic rats’ sensory and motor functions were recovered in some degree. Collectively, this study may shed light on paraplegia treatment in clinics.
基金supported by Ministry of Science and Technology of China(Grants 2017YFC1104001,2017YFC1104002,2020YFC2002804)National Natural Science Foundation of China(Grants 31900980,31970970,31730030,81941011,31971279,31771053,82030035,31900749)+5 种基金Beijing Science and Technology Program(Grant Z181100001818007)Natural Science Foundation of Beijing Municipality(Grant KZ201810025030,7222004)Priority of Shanghai Key Discipline of Medicine(Grant 2017ZZ02020)Foundation of Shanghai Municipal Education Commission(Grant 2019-01-07-00-07-E00055)the Key R&D Program of Jiangsu(Grant BE2020026)Fundamental Research Funds for Central Public Welfare Research Institutes(Grant 2022CZ-12).
文摘Spinal cord injury(SCI)is a severe damage usually leading to limb dysesthesia,motor dysfunction,and other physiological disability.We have previously shown that NT3-chitosan could trigger an acute SCI repairment in rats and non-human primates.Due to the negative effect of inhibitory molecules in glial scar on axonal regeneration,however,the role of NT3-chitosan in the treatment of chronic SCI remains unclear.Compared with the fresh wound of acute SCI,how to handle the lesion core and glial scars is a major issue related to chronic-SCI repair.Here we report,in a chronic complete SCI rat model,establishment of magnetic resonancediffusion tensor imaging(MR-DTI)methods to monitor spatial and temporal changes of the lesion area,which matched well with anatomical analyses.Clearance of the lesion core via suction of cystic tissues and trimming of solid scar tissues before introducing NT3-chitosan using either a rigid tubular scaffold or a soft gel form led to robust neural regeneration,which interconnected the severed ascending and descending axons and accompanied with electrophysiological and motor functional recovery.In contrast,cystic tissue extraction without scar trimming followed by NT3-chitosan injection,resulted in little,if any regeneration.Taken together,after lesion core clearance,NT3-chitosan can be used to enable chronic-SCI repair and MR-DTI-based mapping of lesion area and monitoring of ongoing regeneration can potentially be implemented in clinical studies for subacute/chronic-SCI repair.
基金the National Natural Science Foundation of China(Grants 81941011,82271403,31730030,82272171,31971279,31900749)Beijing Natural Science Foundation(Grants 7222004,7214301)Beijing Science and Technology Program(Grant Z181100001818007).
文摘Different types of traumatic brain injury(TBI)have posed a hazard to human health for a while,and their aftereffects have a significant negative impact on patients'quality of life.Despite the increased attention that TBI has received recently,the clinical treatment plan that is currently in place only consists of palliative therapy for neuroprotection or the mitigation of secondary injury,which has only a minimally positive impact on the prognosis and quality of life in TBI patients.After TBI,regenerative therapy seeks to improve the patient's function.Cell therapy,which has become one of the hottest research fields,is expected to improve the therapeutic effect of this disease.This article will briefly discuss recent developments in research of TBI and available treatments,and then give a general assessment of the outlook.
