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.

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.

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.

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.