Activation of adult endogenous neurogenesis by a hyaluronic acid collagen gel containing basic fibroblast growth factor promotes remodeling and functional recovery of the injured cerebral cortex

The presence of endogenous neural stem/progenitor cells in the adult mammalian brain suggests that the central nervous system can be repaired and regenerated after injury.However,whether it is possible to stimulate neurogenesis and reconstruct cortical layers II to VI in non-neurogenic regions,such as the cortex,remains unknown.In this study,we implanted a hyaluronic acid collagen gel loaded with basic fibroblast growth factor into the motor cortex immediately following traumatic injury.Our findings reveal that this gel effectively stimulated the proliferation and migration of endogenous neural stem/progenitor cells,as well as their differentiation into mature and functionally integrated neurons.Importantly,these new neurons reconstructed the architecture of cortical layers II to VI,integrated into the existing neural circuitry,and ultimately led to improved brain function.These findings offer novel insight into potential clinical treatments for traumatic cerebral cortex injuries.

Activation of endogenous neurogenesis and angiogenesis by basic fibroblast growth factor-chitosan gel in an adult rat model of ischemic stroke

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.

Visualizing Wallerian degeneration in the corticospinal tract after sensorimotor cortex ischemia in mice

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.

A core scientific problem in the treatment of central nervous system diseases:newborn neurons

It has long been asserted that failure to recover from central nervous system diseases is due to the system's intricate structure and the regenerative incapacity of adult neurons.Yet over recent decades,numerous studies have established that endogenous neurogenesis occurs in the adult central nervous system,including humans'.This has challenged the long-held scientific consensus that the number of adult neurons remains constant,and that new central nervous system neurons cannot be created or renewed.Herein,we present a comprehensive overview of the alterations and regulatory mechanisms of endogenous neurogenesis following central nervous system injury,and describe novel treatment strategies that to rget endogenous neurogenesis and newborn neurons in the treatment of central nervous system injury.Central nervous system injury frequently results in alterations of endogenous neurogenesis,encompassing the activation,proliferation,ectopic migration,diffe rentiation,and functional integration of endogenous neural stem cells.Because of the unfavorable local microenvironment,most activated neural stem cells diffe rentiate into glial cells rather than neurons.Consequently,the injury-induced endogenous neurogenesis response is inadequate for repairing impaired neural function.Scientists have attempted to enhance endogenous neurogenesis using various strategies,including using neurotrophic factors,bioactive materials,and cell reprogramming techniques.Used alone or in combination,these therapeutic strategies can promote targeted migration of neural stem cells to an injured area,ensure their survival and diffe rentiation into mature functional neurons,and facilitate their integration into the neural circuit.Thus can integration re plenish lost neurons after central nervous system injury,by improving the local microenvironment.By regulating each phase of endogenous neurogenesis,endogenous neural stem cells can be harnessed to promote effective regeneration of newborn neurons.This offers a novel approach for treating central nervous system injury.

Chitosan-based thermosensitive hydrogel with long-term release of murine nerve growth factor for neurotrophic keratopathy

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.

Phase Ib trial of camrelizumab combined with chemotherapy and apatinib for neoadjuvant treatment of locally advanced thoracic esophageal squamous cell carcinoma

Objective:This is a prospective,single-arm,phase Ib study to evaluate the safety and efficacy of camrelizumab combined with chemotherapy and apatinib as neoadjuvant therapy for locally advanced thoracic esophageal squamous cell carcinoma(ESCC).Methods:The regimen encompassed 2-4 cycles of neoadjuvant camrelizumab,nab-paclitaxel,nedaplatin,and apatinib to treatment-naive patients with resectable locally advanced ESCC.The treatment was repeated every 14 days.Initially,six patients were planned to receive two cycles of neoadjuvant therapy as safety assessment,and then 24 patients received four cycles of neoadjuvant therapy,followed by esophagectomy after 4-8 weeks.The primary endpoint was safety.The key secondary endpoints were pathologic complete response(pCR)and major pathologic response(MPR).Results:This study enrolled 30 patients,among whom,five patients received two cycles of neoadjuvant therapy,and one patient missed the second cycle of therapy due to grade 3 elevated alanine transaminase(ALT)level.The remaining 24 patients received four planned cycles of neoadjuvant therapy.Eleven patients(36.7%)devel-oped grade 3 neoadjuvant treatment-related adverse events(TRAEs).No patient developed grade 4 or 5 TRAEs.Neutropenia(23.3%)was the most common grade 3 TRAE.Twenty-nine patients underwent esophagectomy af-ter neoadjuvant therapy.Among them,15 patients(51.7%)achieved MPR,including seven patients with pCR(24.1%).Radiographic analyses established a significant correlation between maximal standardized uptake value(SUV max)reduction and pathologic regression(P=0.00095).Conclusions:Neoadjuvant camrelizumab combined with chemotherapy plus apatinib demonstrated a manageable safety profile for patients with locally advanced ESCC,and an encouraging efficacy was observed in most of the treated patients.A decrease in SUV max of the primary tumor may be a predictor of pathologic response to neoadjuvant camrelizumab combined with chemotherapy plus apatinib in ESCC.

Adult Mammalian Neurogenesis:Hopes and Challenges in the Repair of Spinal Cord Injury

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.

Endogenous neurogenesis in adult mammals after spinal cord injury

During the whole life cycle of mammals, new neurons are constantly regenerated in the subgranular zone of the dentate gyms 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 ceils.

An individualized immune signature of pretreatment biopsies predicts pathological complete response to neoadjuvant chemoradiotherapy and outcomes in patients with esophageal squamous cell carcinoma

No clinically available biomarkers can predict pathological complete response(pCR)for esophageal squamous cell carcinomas(ESCCs)with neoadjuvant chemoradiotherapy(nCRT).Considering that antitumor immunity status is an important determinant for nCRT,we performed an integrative analysis of immune-related gene profiles from pretreatment biopsies and constructed the first individualized immune signature for pCR and outcome prediction of ESCCs through a multicenter analysis.During the discovery phase,14 differentially expressed immune-related genes(DEIGs)with greater than a twofold change between pCRs and less than pCRs(<pCRs)were revealed from 28 pretreatment tumors in a Guangzhou cohort using microarray data.Ten DEIGs were verified by qPCR from 30 cases in a Beijing discovery cohort.Then,a four-gene-based immune signature(SERPINE1,MMP12,PLAUR,and EPS8)was built based on the verified DEIGs from 71 cases in a Beijing training cohort,and achieved a high accuracy with an area under the receiver operating characteristic curve(AUC)of 0.970.The signature was further validated in an internal validation cohort and an integrated external cohort(Zhengzhou and Anyang cohorts)with AUCs of 0.890 and 0.859,respectively.Importantly,a multivariate analysis showed that the signature was the only independent predictor for pCR.In addition,patients with high predictive scores showed significantly longer overall and relapse-free survival across multiple centers(P<0.05).This is the first,validated,and clinically applicable individualized immune signature of pCR and outcome prediction for ESCCs with nCRT.Further prospective validation may facilitate the combination of nCRT and immunotherapy.

Chronic spinal cord injury repair by NT3-chitosan only occurs after clearance of the lesion scar

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.

Regeneration strategies after the adult mammalian central nervous system injury—biomaterials

The central nervous system(CNS)has very restricted intrinsic regeneration ability under the injury or disease condition.Innovative repair strategies,therefore,are urgently needed to facilitate tissue regeneration and functional recovery.The published tissue repair/regeneration strategies,such as cell and/or drug delivery,has been demonstrated to have some therapeutic effects on experimental animal models,but can hardly find clinical applications due to such methods as the extremely low survival rate of transplanted cells,difficulty in integrating with the host or restriction of blood-brain barriers to administration patterns.Using biomaterials can not only increase the survival rate of grafts and their integration with the host in the injured CNS area,but also sustainably deliver bioproducts to the local injured area,thus improving the microenvironment in that area.This review mainly introduces the advances of various strategies concerning facilitating CNS regeneration.

Application of the sodium hyaluronate-CNTF scaffolds in repairing adult rat spinal cord injury and facilitating neural network formation

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.

Regeneration and functional recovery of the completely transected optic nerve in adult rats by CNTF-chitosan

Dear Editor,The optic nerve,which belongs to the central nervous system(CNS),cannot regenerate when injured in adult mammals.1 Up to now,no readily translatable measures are available for repairing a severely injured optic nerve.Herein we demonstrated that ciliary neurotrophic factor(CNTF)-chitosan enabled the reconstruction and functional recovery of the adult rat visual system,thus shedding light on the clinical potential for repairing the severely injured optic nerve.

Cellular regeneration treatments for traumatic brain injury

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.