Endogenous Neural Stem Cells Research Articles

Bioactive Peptide Hydrogel Scaffold with High Fluidity, Thermosensitivity, and Neurotropism in 3D Spatial Structure for Promoted Repair of Spinal Cord Injury.

Spinal cord injury (SCI) has been considered a clinically challenging disease that is characterized by local disturbance of the microenvironment, which inhibits post-injury neural regeneration. The simulation of a microenvironment conducive to the regeneration of spinal cord is beneficial for SCI repair. In this study, bioactive composite hydrogels are developed that mimic the regenerative microenvironment of spinal cord for enhanced SCI repair. The fabricated composite hydrogels (CRP) based on chitosan (CS), RADA16 nanofibers, and nerve-promoted peptide (PPFLMLLKGSTR) exhibit excellent injectability, superior biodegradability and biocompatibility. In addition, the CRP hydrogels can formquickly (a few minutes) by mixing three components at human body temperature, showing high potential as a biomimetic matrix for in situ repair of SCI. The in vitro studies demonstrate that the CRP hydrogels can not only promote the proliferation and migration of bone marrow mesenchymal stem cells but also induce the proliferation and differentiation of neural stem cells (NSCs) into neurons. Meanwhile, the hydrogels reveal the efficiency of protecting neurons and promoting axonal growth. Furthermore, the in vivo tests prove that the CRP hydrogels can reduce post-SCI inflammatory responses, inhibit reactive astrocyte over-proliferation, and promote the migration, proliferation, and differentiation of endogenous NSCs, which agree well with the in vitro results. The pre-clinical test demonstrates that the CRP hydrogels restore the motor function in completely transected spinal cord rats, and the SCI repair mechanism may involve the activation of the PI3K/AKT/mTOR pathway. It is believed that the strategies shown in this work will be valuable for the design and synthesis of novel hydrogels for biomedical and tissue engineering applications.

GHRH and its analogues in central nervous system diseases.

Growth hormone-releasing hormone (GHRH) is primarily produced by the hypothalamus and stimulates the release of growth hormone (GH) in the anterior pituitary gland, which subsequently regulates the production of hepatic insulin-like growth factor-1 (IGF-1). GH and IGF-1 have potent effects on promoting cell proliferation, inhibiting cell apoptosis, as well as regulating cell metabolism. In central nerve system (CNS), GHRH/GH/IGF-1 promote brain development and growth, stimulate neuronal proliferation, and regulate neurotransmitter release, thereby participating in the regulation of various CNS physiological activities. In addition to hypothalamus-pituitary gland, GHRH and GHRH receptor (GHRH-R) are also expressed in other brain cells or tissues, such as endogenous neural stem cells (NSCs) and tumor cells. Alternations in GHRH/GH/IGF-1 axis are associated with various CNS diseases, for example, Alzheimer's disease, amyotrophic lateral sclerosis and emotional disorders manifest GHRH, GH or IGF-1 deficiency, and GH or IGF-1 supplementation exerts beneficial therapeutic effects on these diseases. CNS tumors, such as glioma, can express GHRH and GHRH-R, and activating this signaling pathway promotes tumor cell growth. The synthesized GHRH antagonists have shown to inhibit glioma cell growth and may hold promising as an adjuvant therapy for treating glioma. In addition, we have shown that GHRH agonist MR-409 can improve neurological sequelae after ischemic stroke by activating extrapituitary GHRH-R signaling and promoting endogenous NSCs-derived neuronal regeneration. This article reviews the involvement of GHRH/GH/IGF-1 in CNS diseases, and potential roles of GHRH agonists and antagonists in treating CNS diseases.

Nicotinamide Riboside Promotes the Proliferation of Endogenous Neural Stem Cells to Repair Spinal Cord Injury.

Activation of endogenous neural stem cells (NSC) is one of the most potential measures for neural repair after spinal cord injury. However, methods for regulating neural stem cell behavior are still limited. Here, we investigated the effects of nicotinamide riboside promoting the proliferation of endogenous neural stem cells to repair spinal cord injury. Nicotinamide riboside promotes the proliferation of endogenous neural stem cells and regulates their differentiation into neurons. In addition, nicotinamide riboside significantly restored lower limb motor dysfunction caused by spinal cord injury. Nicotinamide riboside plays its role in promoting the proliferation of neural stem cells by activating the Wnt signaling pathway through the LGR5 gene. Knockdown of the LGR5 gene by lentivirus eliminates the effect of nicotinamide riboside on the proliferation of endogenous neural stem cells. In addition, administration of Wnt pathway inhibitors also eliminated the proliferative effect of nicotinamide riboside. Collectively, these findings demonstrate that nicotinamide promotes the proliferation of neural stem cells by targeting the LGR5 gene to activate the Wnt pathway, which provides a new way to repair spinal cord injury.

An injectable decellularized extracellular matrix hydrogel with cortical neuron-derived exosomes enhances tissue repair following traumatic spinal cord injury

Traumatic spinal cord injury (SCI), known for its limited intrinsic regeneration capacity, often results in considerable neurological impairment. Studies suggest that therapeutic techniques utilizing exosomes (Exo) to promote tissue regeneration and modulate immune responses are promising for SCI treatment. However, combining exosome therapy with biomaterials for SCI treatment is not very effective. This study developed an adhesive hydrogel using exosomes secreted by cortical neurons derived from human induced pluripotent stem cells (iPSCs) and decellularized extracellular matrix (dECM) from human umbilical cord mesenchymal stem cells (hUCMSCs) to enhance motor function recovery post-SCI. In vitro assessments demonstrated the excellent cytocompatibility of the dECM hydrogel. Additionally, the Exo-dECM hydrogel facilitated the polarization of early M2 macrophages, reduced neuronal apoptosis, and established a pro-regenerative microenvironment in a rodent SCI model. Subsequent analyses revealed significant activation of endogenous neural stem cells and promotion of axon regeneration and remyelination at eight weeks post-surgery. The Exo-dECM hydrogel also promoted the functional recovery and preservation of urinary tissue in SCI-afflicted rats. These findings highlighted that the Exo-dECM hydrogel is a promising therapeutic strategy for treating SCI.

Neurophilic peptide-reinforced dual-fiber-network bioactive hydrogels for spinal cord injury repair

Spinal cord injury (SCI) is a challenging central nervous system disorder that characterized by microenvironmental disturbances following injury, which can be addressed by simulating the microenvironment of the spinal cord regeneration. Herein, we report the design and synthesis of bioactive hydrogels with a dual-fiber-network (DFN) porous structure, using self-assembled peptide nanofibers (PNFs) and natural cellulose nanofibers (CNFs). A neurophilic peptide is further introduced to enhance nervous regeneration capability of the pre-prepared PNF/CNF hydrogels, which then exhibit excellent neuro-affinity, self-healing ability, biodegradability, and biocompatibility, facilitating targeted SCI repair and regeneration through the hydrogel injection. The in vitro experiments reveal that the DFN hydrogel can enhance the proliferation and migration of bone marrow mesenchymal stem cells, and induce neural stem cell (NSC) proliferation with enhanced neuronal differentiation and axonal growth. Additionally, the in vivo studies validate that the hydrogel attenuates the post-SCI inflammation, inhibits reactive astrocyte proliferation, and facilitates endogenous NSC proliferation and migration, as well as promotes neuronal growth and axonal regeneration. The potential mechanism of SCI repair is ascribed to the hydrogel-induced activation of the PI3K/AKT/mTOR pathway, which alleviates inflammatory response, inhibits excessive reactive response of glial cells, and promotes NSC differentiation into neurons. This neurophilic peptide-reinforced DFN bioactive hydrogel system, with its comprehensive approach to SCI repair, holds great potential for clinical applications.

Metformin enhances endogenous neural stem cells proliferation, neuronal differentiation, and inhibits ferroptosis through activating AMPK pathway after spinal cord injury

BackgroundInadequate nerve regeneration and an inhibitory local microenvironment are major obstacles to the repair of spinal cord injury (SCI). The activation and differentiation fate regulation of endogenous neural stem cells (NSCs) represent one of the most promising repair approaches. Metformin has been extensively studied for its antioxidative, anti-inflammatory, anti-aging, and autophagy-regulating properties in central nervous system diseases. However, the effects of metformin on endogenous NSCs remains to be elucidated.MethodsThe proliferation and differentiation abilities of NSCs were evaluated using CCK-8 assay, EdU/Ki67 staining and immunofluorescence staining. Changes in the expression of key proteins related to ferroptosis in NSCs were detected using Western Blot and immunofluorescence staining. The levels of reactive oxygen species, glutathione and tissue iron were measured using corresponding assay kits. Changes in mitochondrial morphology and membrane potential were observed using transmission electron microscopy and JC-1 fluorescence probe. Locomotor function recovery after SCI in rats was assessed through BBB score, LSS score, CatWalk gait analysis, and electrophysiological testing. The expression of the AMPK pathway was examined using Western Blot.ResultsMetformin promoted the proliferation and neuronal differentiation of NSCs both in vitro and in vivo. Furthermore, a ferroptosis model of NSCs using erastin treatment was established in vitro, and metformin treatment could reverse the changes in the expression of key ferroptosis-related proteins, increase glutathione synthesis, reduce reactive oxygen species production and improve mitochondrial membrane potential and morphology. Moreover, metformin administration improved locomotor function recovery and histological outcomes following SCI in rats. Notably, all the above beneficial effects of metformin were completely abolished upon addition of compound C, a specific inhibitor of AMP-activated protein kinase (AMPK).ConclusionMetformin, driven by canonical AMPK-dependent regulation, promotes proliferation and neuronal differentiation of endogenous NSCs while inhibiting ferroptosis, thereby facilitating recovery of locomotor function following SCI. Our study further elucidates the protective mechanism of metformin in SCI, providing new mechanistic insights for its candidacy as a therapeutic agent for SCI.

A Study on the Role of miR-126 in the Repair Process after Spinal Cord Injury

Background: Spinal Cord Injury (SCI) results in motor, sensory, and autonomic dysfunctions and causes social and economic problems. Surgery, medication, and stem cell transplantation are therapeutic strategies for SCI. The use of endogenous neural stem cells seems preferable due to their lower immune responses. miR-126 serves as a promising microRNA for reducing inflammation after SCI. It can promote angiogenesis and proliferation of neural stem cells Objectives: This study aimed to observe changes in miR-126 expression after SCI in an animal mice model. Methods: A total of 42 healthy adult FVB mice were divided equally into 7 groups (6 SCI model versus 1 control). At different periods following SCI establishment in the model groups, Basso Mouse Scale score (BMS), histopathological changes, and expression levels of miR-126 were evaluated in the model groups compared to the control one. Results:: The BMS score increased to a certain extent as the time after spinal cord injury progressed. HE and Nissl staining showed that the acute period (1-7 days) after spinal cord injury was characterized by neuronal loss, whereas the chronic phase (21st day) was characterized by scar and cavity formation. Compared with the control group, the model group exhibited decreased expression of miR-126 during the acute phase (days 1-7 post-SCI). However, its expression increased by 21th day after SCI. Conclusion: Overexpressed miR-126 can contribute to reduced SCI-related damages, which may result in the promotion of the growth and proliferation of neural stem cells as well as the repair of motor function.

Apelin Receptor Homodimerisation Inhibits Hippocampal Neuronal Autophagy via G Protein-Dependent Signalling in Vascular Dementia.

Vascular dementia (VD), a progressive vascular cognitive impairment, is characterised by the presence of cerebral hypoperfusion, increased blood-brain barrier permeability, and white matter lesions. Although current treatment strategies primarily focus on risk factors such as hypertension, diabetes, and heart disease, efficient and targeted therapies are lacking and the underlying mechanisms of VD remain unclear. We previously discovered that Apelin receptors (APJ), which are G protein-coupled receptors (GPCRs), can homodimerize and generate signals that are distinct from those of APJ monomers in VD rats. Apelin-13 reduces the level of APJ homodimers and leads to the proliferation of endogenous neural stem cells in the hippocampal dentate gyrus area, suggesting that it has a neuroprotective role. In this study, we established a rat and cellular oxygen-glucose deprivation/reoxygenation VD model to investigate the impact of APJ homodimerisation on autophagy. We found that APJ homodimers protect against VD by inhibiting autophagy through the Gαq and PI3K/Akt/mTOR pathways upon Gαi signalling, both in vivo and in vitro. This discovery provides a promising therapeutic target for chronic cerebral ischaemia-reperfusion diseases and an experimental foundation for the development of drugs that target APJ homodimers.

Digirseophene A promotes recovery in injured developing cerebellum via AMPK/AKT/GSK3β pathway-mediated neural stem cell proliferation

Neural stem cells (NSCs) exhibit a remarkable capacity for self-renewal and have the potential to differentiate into various neural lineage cells, which makes them pivotal in the management of neurological disorders. Harnessing the inherent potential of endogenous NSCs for enhancing nerve repair and regeneration represents an optimal approach to addressing diseases of the nervous system. In this study, we explored the potential of a novel benzophenone derivative named Digirseophene A (DGA), which was isolated from the endophytic fungus Corydalis tomentella. Previous experiments have extensively identified and characterized DGA, revealing its unique properties. Our findings demonstrate the remarkable capability of DGA to stimulate neural stem cell proliferation, both in vitro and in vivo. Furthermore, we established a model of radiation-induced cerebellar injury to assess the effects of DGA on the distribution of different cell subpopulations within the damaged cerebellum, thereby suggesting its beneficial role in cerebellar repair. In addition, our observations on a primary NSCs model revealed that DGA significantly increased cellular oxygen consumption, indicating increased energy and metabolic demands. By utilizing various pathway inhibitors in combination with DGA, we successfully demonstrated its ability to counteract the suppressive impacts of AMPK and GSK3β inhibitors on NSC proliferation. Collectively, our research results strongly suggest that DGA, as an innovative compound, exerts its role in activating NSCs and promoting injury repair through the regulation of the AMPK/AKT/GSK3β pathway.

New Insights into the Role of Mild Hypoxia in Regulating Neural Stem Cell Characteristics.

The proliferation of neural stem cells (NSCs) is precisely regulated by extracellular environmental factors. In situ hypoxia, one of the key factors involved in the regulation of NSC characteristics, has attracted increasing amounts of attention. Numerous studies have demonstrated that hypoxia can significantly promote the formation of neurospheres and the proliferation of NSCs in vitro and that intermittent hypoxia can promote the proliferation of endogenous NSCs invivo. In this article, the effects of different concentrations of oxygen on NSC proliferation and differentiation both invivo and in vitro are reviewed, and the potential applications of hypoxia-preconditioned NSCs, as well as research progress and challenges in the treatment of central nervous system diseases, are further summarized. Here, the critical role of oxygen in the neurogenesis of NSCs is emphasized, and insights into the use of hypoxia to regulate NSC characteristics are provided.

Neuraminidase inhibition promotes the collective migration of neurons and recovery of brain function

In the injured brain, new neurons produced from endogenous neural stem cells form chains and migrate to injured areas and contribute to the regeneration of lost neurons. However, this endogenous regenerative capacity of the brain has not yet been leveraged for the treatment of brain injury. Here, we show that in healthy brain chains of migrating new neurons maintain unexpectedly large non-adherent areas between neighboring cells, allowing for efficient migration. In instances of brain injury, neuraminidase reduces polysialic acid levels, which negatively regulates adhesion, leading to increased cell–cell adhesion and reduced migration efficiency. The administration of zanamivir, a neuraminidase inhibitor used for influenza treatment, promotes neuronal migration toward damaged regions, fosters neuronal regeneration, and facilitates functional recovery. Together, these findings shed light on a new mechanism governing efficient neuronal migration in the adult brain under physiological conditions, pinpoint the disruption of this mechanism during brain injury, and propose a promising therapeutic avenue for brain injury through drug repositioning.

Relationship Between the Migration of Endogenous Neural Stem Cells and the Pattern of Change in Immune Cell Phenotypes in the Microenvironment After Intracerebral Hemorrhage in Rats

Intracerebral hemorrhage (ICH), the second most common type of stroke, can cause long-lasting disability in the afflicted patients. The study was conducted to examine the patterns of change in endogenous neural stem cells (eNSCs) and in the regenerative microenvironment after ICH, to observe the relationship between the migration of eNSCs and the pattern of change in the polarization state of immune cells in the microenvironment, and provide a research basis for research on clinical nerve repair. The collagenase injection method was used for modeling. The ICH model was induced in adult female Sprague-Dawley (SD) rats by injecting type VII collagenase (2 U) into the brain tissue of rats. All the experimental rats weighed 280-300 g. In order to simulate the ICU at different time points, including the acute phase (within 1 week), subacute phase (1-3 weeks), and the chronic phase (over 3 weeks), brain tissues were harvested at 3 day post injection (3 DPI), 10 DPI, 20 DPI, and 30 DPI to evaluate the modeling effect. Immunofluorescence staining of the brain tissue sections was performed with DCX antibody to observe the pattern of change in the migration of eNSCs in the brain tissue at different time points. Immunofluorescence staining of brain tissue sections was performed with CD206 antibody and CD86 antibody for respective observation of the pattern of change in pro-inflammatory (M1-type) and anti-inflammatory (M2-type) immune cells in the regenerative microenvironment of the brain tissue after ICM. Spontaneous ICH was successfully induced by injecting type Ⅶ collagenase into the brain tissue of SD rats. The volume of the hematoma formed started to gradually increase at 3 DPI and reached its maximum at 10 DPI. After that, the hematoma was gradually absorbed and was completely absorbed by 30 DPI. Analysis of the pattern of changes in eNSCs in the brain tissue showed that a small number of eNSCs were activated at 3 DPI, but very soon their number started to decrease. By 10 DPI, eNSCs gradually began to increase. A large number of eNSCs migrated to the hemorrhage site at 20 DPI. Then the number of eNSCs decreased significantly at 30 DPI (P<0.01). Analysis of the immune microenvironment of the brain tissue showed that pro-inflammatory (M1 type) immune cells increased significantly at 10 and 20 DPI (P<0.01) and decreased at 30 DPI. Anti-inflammatory (M2 type) immune cells began to increase gradually at 3 DPI, decreased significantly at 20 DPI (P<0.05), and then showed an increase at 30 DPI. After ICH in rats, eNSCs migrating toward the site of ICH first increase and then decrease. The immune microenvironment demonstrates a pattern of change in which inflammation is suppressed at first, then promoted, and finally suppressed again. Inflammation may have a stimulatory effect on the migration of eNSCs, but excessive inflammatory activation has an inhibitory effect on the differentiation and further activation of eNSCs. After ICH, the early stage of repair and protection (10 d) and the subacute phase (20 d) may provide the best opportunities for intervention.

Injectable Hydrogel Loaded with CDs and FTY720 Combined with Neural Stem Cells for the Treatment of Spinal Cord Injury.

Spinal cord injury (SCI) is an incurable and disabling event that is accompanied by complex inflammation-related pathological processes, such as the production of excessive reactive oxygen species (ROS) by infiltrating inflammatory immune cells and their release into the extracellular microenvironment, resulting in extensive apoptosis of endogenous neural stem cells. In this study, we noticed the neuroregeneration-promoting effect as well as the ability of the innovative treatment method of FTY720-CDs@GelMA paired with NSCs to increase motor function recovery in a rat spinal cord injury model. Carbon dots (CDs) and fingolimod (FTY720) were added to a hydrogel created by chemical cross-linking GelMA (FTY720-CDs@GelMA). The basic properties of FTY720-CDs@GelMA hydrogels were investigated using TEM, SEM, XPS, and FTIR. The swelling and degradation rates of FTY720-CDs@GelMA hydrogels were measured, and each group's ability to scavenge reactive oxygen species was investigated. The in vitro biocompatibility of FTY720-CDs@GelMA hydrogels was assessed using neural stem cells. The regeneration of the spinal cord and recovery of motor function in rats were studied following co-treatment of spinal cord injury using FTY720-CDs@GelMA hydrogel in combination with NSCs, utilising rats with spinal cord injuries as a model. Histological and immunofluorescence labelling were used to determine the regeneration of axons and neurons. The recovery of motor function in rats was assessed using the BBB score. The hydrogel boosted neurogenesis and axonal regeneration by eliminating excess ROS and restoring the regenerative environment. The hydrogel efficiently contained brain stem cells and demonstrated strong neuroprotective effects in vivo by lowering endogenous ROS generation and mitigating ROS-mediated oxidative stress. In a follow-up investigation, we discovered that FTY720-CDs@GelMA hydrogel could dramatically boost NSC proliferation while also promoting neuronal regeneration and synaptic formation, hence lowering cavity area. Our findings suggest that the innovative treatment of FTY720-CDs@GelMA paired with NSCs can effectively improve functional recovery in SCI patients, making it a promising therapeutic alternative for SCI.

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 target 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, differentiation, and functional integration of endogenous neural stem cells. Because of the unfavorable local microenvironment, most activated neural stem cells differentiate 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 differentiation into mature functional neurons, and facilitate their integration into the neural circuit. Thus can integration replenish 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.

250 Harnessing the Endogenous Stem Cell Response After Spinal Cord Injury: A Novel and Translationally Relevant Therapeutic Strategy

INTRODUCTION: The adult spinal cord contains a population of endogenous ependymal-derived neural stem/progenitor cells (epNSPCs) that hold the potential to promote regeneration and repair after injury. epNSPCs are normally quiescent but are acutely activated after spinal cord injury (SCI). Despite this, the activation of these cells remains insufficient to promote robust neural regeneration and recovery. Understanding the mechanisms that govern the biology of epNSPCs is critical in developing a therapeutic strategy to harness their regenerative potential after SCI. METHODS: epNSPCs isolated from the adult spinal cord were used for in vitro mechanistic analysis. In vivo, cervical SCI was induced in adult rodents using a clinically relevant compression-contusion model of cervical SCI. FoxJ1-Cre-tdT reporter mice were used for lineage tracing studies. One-week post-SCI, animals (n = 15/group) were randomized to receive CX546 (a positive AMPA receptor modulator), or vehicle-control. Animals underwent weekly behavioural testing and spinal cords were extracted for histological/molecular analysis. RESULTS: Glutamate excitotoxicity, a hallmark in the pathogenesis of acute SCI, leads to calcium influx in spinal cord epNSPCs via AMPA receptors (AMPARs) and this change in calcium in concert with Notch signaling drives their proliferation and astrocytic differentiation. Blockade of AMPARs in vivo inhibits the activation of epNSPCs post-SCI. Positive modulation of AMPARs after SCI using the clinically relevant class of drugs known as ampakines, enhances epNSPC proliferation, increases pro-regenerative astrocytes and neurotrophic factor production, and promotes neuronal survival and motor recovery. CONCLUSIONS: We report on a novel mechanism by which AMPARs regulate the growth and phenotype of endogenous epNSPCs. Pharmacological targeting of this mechanism could be used to harness the regenerative potential of endogenous neural stem cells and improve motor recovery after SCI.

Mapping knowledge of the stem cell in traumatic brain injury: a bibliometric and visualized analysis.

Traumatic brain injury (TBI) is a brain function injury caused by external mechanical injury. Primary and secondary injuries cause neurological deficits that mature brain tissue cannot repair itself. Stem cells can self-renewal and differentiate, the research of stem cells in the pathogenesis and treatment of TBI has made significant progress in recent years. However, numerous articles must be summarized to analyze hot spots and predict trends. This study aims to provide a panorama of knowledge and research hotspots through bibliometrics. We searched in the Web of Science Core Collection (WoSCC) database to identify articles pertaining to TBI and stem cells published between 2000 and 2022. Visualization knowledge maps, including co-authorship, co-citation, and co-occurrence analysis were generated by VOSviewer, CiteSpace, and the R package "bibliometrix." We retrieved a total of 459 articles from 45 countries. The United States and China contributed the majority of publications. The number of publications related to TBI and stem cells is increasing yearly. Tianjin Medical University was the most prolific institution, and Professor Charles S. Cox, Jr. from the University of Texas Health Science Center at Houston was the most influential author. The Journal of Neurotrauma has published the most research articles on TBI and stem cells. Based on the burst references, "immunomodulation," "TBI," and "cellular therapy" have been regarded as research hotspots in the field. The keywords co-occurrence analysis revealed that "exosomes," "neuroinflammation," and "microglia" were essential research directions in the future. Research on TBI and stem cells has shown a rapid growth trend in recent years. Existing studies mainly focus on the activation mechanism of endogenous neural stem cells and how to make exogenous stem cell therapy more effective. The combination with bioengineering technology is the trend in this field. Topics related to exosomes and immune regulation may be the future focus of TBI and stem cell research.

Transplantation of Neural Stem Cells Loaded in an IGF-1 Bioactive Supramolecular Nanofiber Hydrogel for the Effective Treatment of Spinal Cord Injury.

Spinal cord injury (SCI) leads to massive cell death, disruption, and demyelination of axons, resulting in permanent motor and sensory dysfunctions. Stem cell transplantation is a promising therapy for SCI. However, owing to the poor microenvironment that develops following SCI, the bioactivities of these grafted stem cells are limited. Cell implantation combined with biomaterial therapies is widely studied for the development of tissue engineering technology. Herein, an insulin-like growth factor-1 (IGF-1)-bioactive supramolecular nanofiber hydrogel (IGF-1 gel) is synthesized that can activate IGF-1 downstream signaling, prevent the apoptosis of neural stem cells (NSCs), improve their proliferation, and induce their differentiation into neurons and oligodendrocytes. Moreover, implantation of NSCs carried out with IGF-1 gels promotes neurite outgrowth and myelin sheath regeneration at lesion sites following SCI. In addition, IGF-1 gels can enrich extracellular vesicles (EVs) derived from NSCs or from nerve cells differentiated from these NSCs via miRNAs related to axonal regeneration and remyelination, even in an inflammatory environment. These EVs are taken up by autologous endogenous NSCs and regulate their differentiation. This study provides adequate evidence that combined treatment with NSCs and IGF-1 gels is a potential therapeutic strategy for treating SCI.

Extracellular vesicles from UTX-knockout endothelial cells boost neural stem cell differentiation in spinal cord injury

BackgroundVascular endothelial cells are pivotal in the pathophysiological progression following spinal cord injury (SCI). The UTX (Ubiquitously Transcribed Tetratripeptide Repeat on Chromosome X) serves as a significant regulator of endothelial cell phenotype. The manipulation of endogenous neural stem cells (NSCs) offers a compelling strategy for the amelioration of SCI.MethodsTwo mouse models were used to investigate SCI: NSCs lineage-traced mice and mice with conditional UTX knockout (UTX KO) in endothelial cells. To study the effects of UTX KO on neural differentiation, we harvested extracellular vesicles (EVs) from both UTX KO spinal cord microvascular endothelial cells (SCMECs) and negative control SCMECs. These EVs were then employed to modulate the differentiation trajectory of endogenous NSCs in the SCI model.ResultsIn our NSCs lineage-traced mice model of SCI, a marked decrease in neurogenesis was observed post-injury. Notably, NSCs in UTX KO SCMECs mice showed enhanced neuronal differentiation compared to controls. RNA sequencing and western blot analyses revealed an upregulation of L1 cell adhesion molecule (L1CAM), a gene associated with neurogenesis, in UTX KO SCMECs and their secreted EVs. This aligns with the observed promotion of neurogenesis in UTX KO conditions. In vivo administration of L1CAM-rich EVs from UTX KO SCMECs (KO EVs) to the mice significantly enhanced neural differentiation. Similarly, in vitro exposure of NSCs to KO EVs resulted in increased activation of the Akt signaling pathway, further promoting neural differentiation. Conversely, inhibiting Akt phosphorylation or knocking down L1CAM negated the beneficial effects of KO EVs on NSC neuronal differentiation.ConclusionsIn conclusion, our findings substantiate that EVs derived from UTX KO SCMECs can act as facilitators of neural differentiation following SCI. This study not only elucidates a novel mechanism but also opens new horizons for therapeutic interventions in the treatment of SCI.1C6MBiJnKEY-9R1wsAiwJtVideo Graphical

Multifunctional Conductive and Electrogenic Hydrogel Repaired Spinal Cord Injury via Immunoregulation and Enhancement of Neuronal Differentiation.

Spinal cord injury (SCI) is a refractory neurological disorder. Due to the complex pathological processes, especially the secondary inflammatory cascade and the lack of intrinsic regenerative capacity, it is difficult to recover neurological function after SCI. Meanwhile, simulating the conductive microenvironment of the spinal cord reconstructs electrical neural signal transmission interrupted by SCI and facilitates neural repair. Therefore, a double-crosslinked conductive hydrogel (BP@Hydrogel) containing black phosphorus nanoplates (BP) is synthesized. When placed in a rotating magnetic field (RMF), the BP@Hydrogel can generate stable electrical signals and exhibit electrogenic characteristic. In vitro, the BP@Hydrogel shows satisfactory biocompatibility and can alleviate the activation of microglia. When placed in the RMF, it enhances the anti-inflammatory effects. Meanwhile, wireless electrical stimulation promotes the differentiation of neural stem cells (NSCs) into neurons, which is associated with the activation of the PI3K/AKT pathway. In vivo, the BP@Hydrogel is injectable and can elicit behavioral and electrophysiological recovery in complete transected SCI mice by alleviating the inflammation and facilitating endogenous NSCs to form functional neurons and synapses under the RMF. The present research develops a multifunctional conductive and electrogenic hydrogel for SCI repair by targeting multiple mechanisms including immunoregulation and enhancement of neuronal differentiation.

The m6A methylation and expression profiles of mouse neural stem cells after hypoxia/reoxygenation

BackgroundIschemia–reperfusion injury to the central nervous system often causes severe complications. The activation of endogenous neural stem cells (NSCs) is considered a promising therapeutic strategy for nerve repair. However, the specific biological processes and molecular mechanisms of NSC activation remain unclear, and the role of N6-methyladenosine (m6A) methylation modification in this process has not been explored.MethodsNSCs were subjected to hypoxia/reoxygenation (H/R) to simulate ischemia–reperfusion in vivo. m6A RNA methylation quantitative kit was used to measure the total RNA m6A methylation level. Quantitative real-time PCR was used to detect methyltransferase and demethylase mRNA expression levels. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA sequencing (RNA-seq) were conducted for NSCs in control and H/R groups, and the sequencing results were analyzed using bioinformatics. Finally, the migration ability of NSCs was identified by wound healing assays, and the proliferative capacity of NSCs was assessed using the cell counting kit-8, EdU assays and cell spheroidization assays.ResultsOverall of m6A modification level and Mettl14 mRNA expression increased in NSCs after H/R treatment. The m6A methylation and expression profiles of mRNAs in NSCs after H/R are described for the first time. Through the joint analysis of MeRIP-seq and RNA-seq results, we verified the proliferation of NSCs after H/R, which was regulated by m6A methylation modification. Seven hub genes were identified to play key roles in the regulatory process. Knockdown of Mettl14 significantly inhibited the proliferation of NSCs. In addition, separate analysis of the MeRIP-seq results suggested that m6A methylation regulates cell migration and differentiation in ways other than affecting mRNA expression. Subsequent experiments confirmed the migration ability of NSCs was suppressed by knockdown of Mettl14.ConclusionThe biological behaviors of NSCs after H/R are closely related to m6A methylation of mRNAs, and Mettl14 was confirmed to be involved in cell proliferation and migration.