JOURNAL/nrgr/04.03/01300535-202603000-00040/figure1/v/2025-06-16T082406Z/r/image-tiff Exogenous neural stem cell transplantation has become one of the most promising treatment methods for chronic stroke. Recent studies have shown that most ischemia-reperfusion model rats recover spontaneously after injury, which limits the ability to observe long-term behavioral recovery. Here, we used a severe stroke rat model with 150 minutes of ischemia, which produced severe behavioral deficiencies that persisted at 12 weeks, to study the therapeutic effect of neural stem cells on neural restoration in chronic stroke. Our study showed that stroke model rats treated with human neural stem cells had long-term sustained recovery of motor function, reduced infarction volume, long-term human neural stem cell survival, and improved local inflammatory environment and angiogenesis. We also demonstrated that transplanted human neural stem cells differentiated into mature neurons in vivo , formed stable functional synaptic connections with host neurons, and exhibited the electrophysiological properties of functional mature neurons, indicating that they replaced the damaged host neurons. The findings showed that human fetal-derived neural stem cells had long-term effects for neurological recovery in a model of severe stroke, which suggests that human neural stem cells-based therapy may be effective for repairing damaged neural circuits in stroke patients.

Adult hippocampal neurogenesis is linked to memory formation in the adult brain, with new neurons in the hippocampus exhibiting greater plasticity during their immature stages compared to mature neurons. Abnormal adult hippocampal neurogenesis is closely associated with cognitive impairment in central nervous system diseases. Targeting and regulating adult hippocampal neurogenesis have been shown to improve cognitive deficits. This review aims to expand the current understanding and prospects of targeting neurogenesis in the treatment of cognitive impairment. Recent research indicates the presence of abnormalities in AHN in several diseases associated with cognitive impairment, including cerebrovascular diseases, Alzheimer's disease, aging-related conditions, and issues related to anesthesia and surgery. The role of these abnormalities in the cognitive deficits caused by these diseases has been widely recognized, and targeting AHN is considered a promising approach for treating cognitive impairment. However, the underlying mechanisms of this role are not yet fully understood, and the effectiveness of targeting abnormal adult hippocampal neurogenesis for treatment remains limited, with a need for further development of treatment methods and detection techniques. By reviewing recent studies, we classify the potential mechanisms of adult hippocampal neurogenesis abnormalities into four categories: immunity, energy metabolism, aging, and pathological states. In immunity-related mechanisms, abnormalities in meningeal, brain, and peripheral immunity can disrupt normal adult hippocampal neurogenesis. Lipid metabolism and mitochondrial function disorders are significant energy metabolism factors that lead to abnormal adult hippocampal neurogenesis. During aging, the inflammatory state of the neurogenic niche and the expression of aging-related microRNAs contribute to reduced adult hippocampal neurogenesis and cognitive impairment in older adult patients. Pathological states of the body and emotional disorders may also result in abnormal adult hippocampal neurogenesis. Among the current strategies used to enhance this form of neurogenesis, physical therapies such as exercise, transcutaneous electrical nerve stimulation, and enriched environments have proven effective. Dietary interventions, including energy intake restriction and nutrient optimization, have shown efficacy in both basic research and clinical trials. However, drug treatments, such as antidepressants and stem cell therapy, are primarily reported in basic research, with limited clinical application. The relationship between abnormal adult hippocampal neurogenesis and cognitive impairment has garnered widespread attention, and targeting the former may be an important strategy for treating the latter. However, the mechanisms underlying abnormal adult hippocampal neurogenesis remain unclear, and treatments are lacking. This highlights the need for greater focus on translating research findings into clinical practice.

Ischemic stroke is a significant global health crisis, frequently resulting in disability or death, with limited therapeutic interventions available. Although various intrinsic reparative processes are initiated within the ischemic brain, these mechanisms are often insufficient to restore neuronal functionality. This has led to intensive investigation into the use of exogenous stem cells as a potential therapeutic option. This comprehensive review outlines the ontogeny and mechanisms of activation of endogenous neural stem cells within the adult brain following ischemic events, with focus on the impact of stem cell-based therapies on neural stem cells. Exogenous stem cells have been shown to enhance the proliferation of endogenous neural stem cells via direct cell-to-cell contact and through the secretion of growth factors and exosomes. Additionally, implanted stem cells may recruit host stem cells from their niches to the infarct area by establishing so-called "biobridges." Furthermore, xenogeneic and allogeneic stem cells can modify the microenvironment of the infarcted brain tissue through immunomodulatory and angiogenic effects, thereby supporting endogenous neuroregeneration. Given the convergence of regulatory pathways between exogenous and endogenous stem cells and the necessity for a supportive microenvironment, we discuss three strategies to simultaneously enhance the therapeutic efficacy of both cell types. These approaches include: (1) co-administration of various growth factors and pharmacological agents alongside stem cell transplantation to reduce stem cell apoptosis; (2) synergistic administration of stem cells and their exosomes to amplify paracrine effects; and (3) integration of stem cells within hydrogels, which provide a protective scaffold for the implanted cells while facilitating the regeneration of neural tissue and the reconstitution of neural circuits. This comprehensive review highlights the interactions and shared regulatory mechanisms between endogenous neural stem cells and exogenously implanted stem cells and may offer new insights for improving the efficacy of stem cell-based therapies in the treatment of ischemic stroke.

Ischemic stroke (IS), a cerebrovascular disease, is the leading cause of physical disability and death worldwide. Tissue plasminogen activator (tPA) and thrombectomy are limited by a narrow therapeutic time window. Although strategies such as drug therapies and cellular therapies have been used in preclinical trials, some important issues in clinical translation have not been addressed: low stem cell survival and drug delivery limited by the blood-brain barrier (BBB). Among the therapeutic options currently sought, carrier-based hydrogels hold great promise for the repair and regeneration of neural tissue in the treatment of ischemic stroke. The advantage lies in the ability to deliver drugs and cells to designated parts of the brain in an injectable manner to enhance therapeutic efficacy. Here, this article provides an overview of the use of carrier-based hydrogels in ischemic stroke therapy and focuses on the use of hydrogel scaffolds containing bioactive molecules and stem cells. In addition to this, we provide a more in-depth summary of the composition, physicochemical properties and physiological functions of the materials themselves. Finally, we also outline the prospects and challenges for clinical translation of hydrogel therapy for IS.

Hypoxic-ischemic encephalopathy (HIE) is a leading cause of neurodevelopmental morbidities in full-term infants. There is strong evidence of sexual differences in hypoxic-ischemic (HI) injury where male neonates are at higher risk as they are subject to more pronounced neurological deficits and death than females. The cellular and molecular mechanisms underlying these sexual discrepancies in HI injury are poorly understood. Mitochondrial dysregulation has been increasingly explored in brain diseases and represents a major target during HI events. In this review, we discuss (1) different mitochondrial functions in the central nervous system (2), mitochondrial dysregulation in the context of HI injury (3), sex-dependent mitochondrial pathways in HIE and (4) modeling of mitochondrial dysfunction using human brain organoids. Gaining insight into these novel aspects of mitochondrial function will offer valuable understanding of brain development and neurological disorders such as HI injury, paving the way for the discovery and creation of new treatment approaches.

Neonatal brains are particularly vulnerable to oxidative stress, making the pentose phosphate pathway (PPP) pivotal in damage limitation. This study aimed to confirm the mechanism of erythropoietin combined with therapeutic hypothermia (TH) in hypoxic-ischemic brain damage (HIBD). Neonatal HIBD rat models were employed and the impacts of erythropoietin and TH on behavior, cerebral infarction, pathology, and microvascular were evaluated. Following that, the assessments of inflammation, oxidative stress, apoptosis, and the level of glucose-6-phosphate dehydrogenase (G6PD, rate-limiting enzyme in the PPP) proceeded. Human brain microvascular endothelial cells (HBMECs) underwent oxygen-glucose deprivation (OGD) and were treated with TH and G6PD inhibitor RRx-001. The impacts of the G6PD inhibitor on HBMEC function and barrier were evaluated. Simultaneous administration of TH and EPO reduced pathological damage and attenuated microvascular loss. In addition, this combination therapy had anti-inflammatory, antioxidant, and anti-apoptotic properties, and enhanced G6PD activity, both in vivo and in vitro. Inhibition of G6PD disrupted the protective effects of TH and EPO on the patency of the PPP and the function of HBMECs, and barrier integrity was further broken. This study reveals that the combination of TH and EPO mitigates microvascular endothelial cell dysfunction via partially modulating the PPP, thus preserving barrier integrity.

The angiogenic response is essential for the repair of ischemic brain tissue. Integrin α6 (Itga6) expression has been shown to increase under hypoxic conditions and is expressed exclusively in vascular structures; however, its role in post-ischemic angiogenesis remains poorly understood. In this study, we demonstrate that mice with endothelial cell-specific knockout of Itga6 exhibit reduced neovascularization, reduced pericyte coverage on microvessels, and accelerated breakdown of microvascular integrity in the peri-infarct area. In vitro, endothelial cells with ITGA6 knockdown display reduced proliferation, migration, and tube-formation. Mechanistically, we demonstrated that ITGA6 regulates post-stroke angiogenesis through the PI3K/Akt-eNOS-VEGFA axis. Importantly, the specific overexpression of Itga6 in endothelial cells significantly enhanced neovascularization and enhanced the integrity of microvessels, leading to improved functional recovery. Our results suggest that endothelial cell Itga6 plays a crucial role in key steps of post-stroke angiogenesis, and may represent a promising therapeutic target for promoting recovery after stroke.

This study aims to elucidate the mitigating effects of the volatile oil of Acori tatarinowii rhizoma (ATR) on dementia, in order to provide a reference for future research and applications of the volatile oil of ATR in the field of dementia.

A search strategy was developed using terms such as "Acori tatarinowii rhizoma," "Acorus tatarinowii Schott," "Asarone," and "Dementia." The literature search was conducted in PubMed, Web of Science, and Google Scholar, and studies not meeting the inclusion criteria were excluded. This study summarizes the main metabolites, active ingredients, toxicological properties, and pharmacokinetic characteristics of the volatile oil from ATR in mitigating dementia, with a particular focus on its potential mechanisms of action. Furthermore, the study highlights the limitations of existing research and offers insights into future research directions.

The volatile oil of ATR mitigates dementia through multiple pathways, including reducing abnormal protein aggregation, promoting neurogenesis, inhibiting neuronal apoptosis, regulating neurotransmitters, improving synaptic function, modulating autophagy, countering cellular stress, reducing neuroinflammation, and alleviating vascular risk factors.

The multi-pathway pharmacological effects of the volatile oil of ATR are well-aligned with the complex mechanisms of dementia progression, highlighting its significant therapeutic potential for anti-dementia applications. This provides new perspectives for the development of more effective anti-dementia drugs. Nonetheless, further rigorous and high-quality preclinical and clinical investigations are required to address key issues, including the chemical characterization of the volatile oil of ATR, potential synergistic effects among active ingredients, toxicity profiles, and definitive clinical efficacy.

Brain decellularized extracellular matrix (ECM) can be an attractive scaffold capable of mimicking the native ecosystem of the central nervous system tissue. We studied the in vitro response of neural cultures exposed to region-specific brain decellularized ECM scaffolds from three distinct neuroanatomical sections: cortex, cerebellum and remaining areas. First, each brain region was evaluated with the isotropic fractionator method to understand the cellular composition of the different cerebral areas. Second, the cerebral regions were subjected to the decellularization process and their respective characterization using molecular, histological, and ultrastructural techniques. Third, the levels of neurotrophic factors in the decellularized brain scaffold were analyzed. Fourth, we studied the region-specific brain decellularized ECM as a mimetic platform for the maturation of PC12 cells, as a unidirectional model of differentiation. Finally, in vitro studies were carried out to evaluate the cell recovery capacity of brain decellularized ECM under stroke-mimetic conditions. Our results show that region-specific brain decellularized ECM can serve as a biomimetic scaffold capable of promoting the growth of neural lineage cells and, in addition, it possesses a combination of structural and biochemical signals (e.g., neurotrophic factors) that are capable of inducing cell phenotypic changes and promote viability and cell recovery in a stroke/ischemia model in vitro.

Neonatal hypoxic-ischemic brain injury (HIBI) can lead to white matter damage, which significantly contributes to cognitive dysfunction, emotional disorders, and sensorimotor impairments. Although dexmedetomidine enhances neurobehavioral outcomes, its impact on oligodendrocyte genesis and myelination following hypoxic-ischemic events, as well as the underlying mechanisms, remain poorly understood. Dexmedetomidine was administered 15 min post-HIBI. We assessed neurobehavioral deficits using various tests: surface righting, negative geotaxis, forelimb grip strength, cliff avoidance, sensory reflexes, novel object recognition, T-maze, and three-chamber social interaction. We also investigated the relationship between myelination and neurobehavioral outcomes. Measurements included oligodendrocyte precursor cell (OPC) proliferation and survival 24 h post-injury, early myelination, and oligodendrocyte differentiation by postnatal day 14. Furthermore, we evaluated microglial activation towards the M2 phenotype and the extent of neuroinflammation during the acute phase. Dexmedetomidine significantly ameliorated long-term neurological deficits caused by HIBI. Pearson linear regression analysis revealed a strong correlation between long-term neurological outcomes and myelin maturity. The treatment notably mitigated the long-term deterioration of myelin formation and maturation following HIBI. This protective effect was primarily due to enhanced OPC proliferation and survival post-HIBI during the acute phase and, to a lesser extent, to the modulation of microglial activity towards the M2 phenotype and a reduction in neuroinflammation. Dexmedetomidine offers substantial protection against long-term neurobehavioral disabilities induced by HIBI, primarily by revitalizing the impaired survival and maturation of oligodendrocyte progenitor cells and promoting myelination.

The IKKβ signaling pathway regulates NF-κB, influencing inflammation and cell survival in the brain. Radial glia cells are crucial for hippocampal neurogenesis and cognition. However, the role and mechanisms of IKKβ in modulating radial glia behavior and its impact on memory and neurogenesis remain unclear. Further studies are needed to understand how alterations in this pathway affect hippocampal function.

The role of IKKβ in memory and hippocampal neurogenesis was examined using GFAP-CreERT2/IKKβflox/flox mice with IKKβ knockdown in radial glia cells. IKKβ expression, NSC proliferation, and differentiation were assessed by immunohistochemistry. NF-κB and β-catenin interactions were evaluated by immunoprecipitation. Cultured adult hippocampal NSCs, with IKKβ or β-catenin shRNA transfection, were analyzed by flow cytometry and western blot to examine stem cell characteristics, NF-κB signaling, cell cycle, and β-catenin pathways.

Our results showed IKKβ cKD increased exploratory activity in the open-field and hyperactivity in the Y-maze, as well as enhanced spatial memory in the object location and Morris water maze tests. It also promoted adult hippocampal NSC proliferation by upregulating positive and inhibiting negative cell cycle regulators. Neuronal differentiation was enhanced, affecting β-catenin signaling and NeuroD1 expression. Additionally, IKKβ cKD promoted NSC survival, as shown by decreased cleaved caspase-3 and reduced Bax and cytochrome c in the hippocampus.

These findings suggest that in hippocampal NSCs, IKKβ inhibits locomotion, cognitive function, and adult hippocampal neurogenesis by suppressing the β-catenin signaling, highlighting its key role in decreasing hippocampal neurogenesis and cognitive function through NF-κB signaling in adult NSCs.

Acute brain injuries (ABI) caused by various emergencies can lead to structural and functional damage to brain tissue. Common causes include traumatic brain injury, cerebral hemorrhage, ischemic stroke, and heat stroke. Globally, ABI represent a significant portion of neurosurgical cases. Previous studies have emphasized the significant therapeutic potential of stem cell-derived extracellular vesicles (EVs). Recent research indicates that EVs extracted from resident cells in the central nervous system (CNS) also show therapeutic potential following brain injury. Microglia, as innate immune cells of the CNS, respond to changes in the internal environment by altering their phenotype and secreting EVs that impact various CNS cells, including neurons, astrocytes, oligodendrocytes, endothelial cells, neural stem cells (NSCs), and microglia themselves. Notably, under different external stimuli, microglia can either promote neuronal survival, angiogenesis, and myelin regeneration while reducing glial scarring and inflammation, or they can exert opposite effects. This review summarizes and evaluates the current research findings on how microglia-derived EVs influence various CNS cells after ABI under different external stimuli. It analyzes the interaction mechanisms between EVs and resident CNS cells and discusses potential future research directions and clinical applications.

Neonatal hypoxic-ischemic encephalopathy (HIE) is worsened by autophagy-induced neuronal damage, with SYNPO2 playing a key role in this process. This study investigates the involvement of SYNPO2 in neuronal autophagy and explores the potential of bone marrow mesenchymal stem cells (BMSCs) to alleviate HIE-induced dysfunction by inhibiting SYNPO2-mediated autophagy. Using in vitro and in vivo neonatal HIE models, we observed an upregulation of SYNPO2 expression, accompanied by increased neuronal injury and aggregation of autophagy-related proteins. Intervention with BMSCs effectively reduced SYNPO2 expression, and SYNPO2 depression mitigated neuroautophagic damage and improved neurological dysfunctions. Moreover, SYNPO2 overexpression exacerbated neuroautophagy despite BMSC treatment, while SYNPO2 depletion notably reduced neuroautophagic damage and alleviated cognitive impairments, retaining the neuroprotective efficacy of BMSC treatment. These findings confirm the role of BMSCs in attenuating HIE injury by suppressing neuroautophagy and provide insights into the mechanistic involvement of SYNPO2. Ultimately, this study identifies SYNPO2 as a novel therapeutic target for neonatal HIE and supports the clinical potential of BMSCs in HIE management.

In the last two decades, stem cells (SCs) have attracted considerable interest for their research value and therapeutic potential in many fields, namely in neuroscience. On the other hand, the discovery of adult neurogenesis, the process by which new neurons are generated in the adult brain, challenged the traditional view that the brain is a static structure after development. The recent findings showing that adult neurogenesis has a significant role in brain plasticity, learning and memory, and emotional behavior, together with the fact that it is strongly dependent on several external and internal factors, have sparked more interest in this area. The mechanisms of adult neural stem cell (NSC) regulation, the physiological role of NSC-mediated neuroplasticity throughout life, and the most recent NSC-based therapeutic applications will be concisely reviewed. Noteworthy, due to their multipotency, self-renewal potential, and ability to secrete growth and immunomodulatory factors, NSCs have been mainly suggested for (1) transplantation, (2) neurotoxicology tests, and (3) drug screening approaches. The clinical trials of NSC-based therapy for different neurologic conditions are, nonetheless, mostly in the early phases and have not yet demonstrated conclusive efficacy or safety. Here, we provide an outlook of the major challenges and limitations, as well as some promising directions that could help to move toward stem cell widespread use in the treatment and prevention of several neurological disorders.

Human induced pluripotent stem cells (hiPSCs), similar to embryonic stem cells, are a class of pluripotent stem cells with the potential to differentiate into various kinds of cells. Because the application of hiPSCs obtained by reprogramming patients' somatic cells in the treatment of brain diseases bypasses the ethical constraints on the use of embryonic stem cells and mitigates immune rejection, hiPSCs have profound clinical application prospects. In this review, we first summarized the differentiation methods of hiPSCs into different kinds of neurons, and secondly discussed the application of hiPSCs in several brain disease models, so as to provide a reference for the future application of hiPSCs in the studies and treatment of brain diseases.

JOURNAL/nrgr/04.03/01300535-202502000-00034/figure1/v/2024-05-28T214302Z/r/image-tiff Several studies have found that transplantation of neural progenitor cells (NPCs) promotes the survival of injured neurons. However, a poor integration rate and high risk of tumorigenicity after cell transplantation limits their clinical application. Small extracellular vesicles (sEVs) contain bioactive molecules for neuronal protection and regeneration. Previous studies have shown that stem/progenitor cell-derived sEVs can promote neuronal survival and recovery of neurological function in neurodegenerative eye diseases and other eye diseases. In this study, we intravitreally transplanted sEVs derived from human induced pluripotent stem cells (hiPSCs) and hiPSCs-differentiated NPCs (hiPSC-NPC) in a mouse model of optic nerve crush. Our results show that these intravitreally injected sEVs were ingested by retinal cells, especially those localized in the ganglion cell layer. Treatment with hiPSC-NPC-derived sEVs mitigated optic nerve crush-induced retinal ganglion cell degeneration, and regulated the retinal microenvironment by inhibiting excessive activation of microglia. Component analysis further revealed that hiPSC-NPC derived sEVs transported neuroprotective and anti-inflammatory miRNA cargos to target cells, which had protective effects on RGCs after optic nerve injury. These findings suggest that sEVs derived from hiPSC-NPC are a promising cell-free therapeutic strategy for optic neuropathy.

Neural stem cells (NSCs) have increasingly been recognized as the most promising candidates for cell-based therapies for the central nervous system (CNS) injuries, primarily due to their pluripotent differentiation capabilities, as well as their remarkable secretory and homing properties. In recent years, extensive research efforts have been initiated to explore the therapeutic potential of NSC transplantation for CNS injuries, yielding significant advancements. Nevertheless, owing to the formation of adverse microenvironment at post-injury leading to suboptimal survival, differentiation, and integration within the host neural network of transplanted NSCs, NSC-based transplantation therapies often fall short of achieving optimal therapeutic outcomes. To address this challenge, genetic modification has been developed an attractive strategy to improve the outcomes of NSC therapies. This is mainly attributed to its potential to not only enhance the differentiation capacity of NSCs but also to boost a range of biological activities, such as the secretion of bioactive factors, anti-inflammatory effects, anti-apoptotic properties, immunomodulation, antioxidative functions, and angiogenesis. Furthermore, genetic modification empowers NSCs to play a more robust neuroprotective role in the context of nerve injury. In this review, we will provide an overview of recent advances in the roles and mechanisms of NSCs genetically modified with various therapeutic genes in the treatment of neural injuries and neural disorders. Also, an update on current technical parameters suitable for NSC transplantation and functional recovery in clinical studies are summarized.

Atrazine (AT), a widely utilized chemical herbicide, causes widespread contamination of agricultural water bodies. Recently, exposure to AT has been linked to the development of age-related neurodegenerative diseases (NDs), suggesting its neurotoxicity potential. As an endocrine disruptor, AT targets the hypothalamus, a crucial part of the neuroendocrine system. However, the toxicological mechanism of AT exposure to the hypothalamus and its correlation with ND development remain unexplored. Our results indicated that AT exposure caused significant morphological and structural damage to the hypothalamus, leading to the loss of mature and intact neurons and microglial activation. Furthermore, hypothalamic neural stem cells (HtNSCs) were recruited to areas of neuronal damage caused by AT. Through in vivo and in vitro experiments, we clarified the outcomes of AT-induced HtNSC recruitment alongside the loss of mature/intact neurons. Mechanistically, AT induces senescence in these recruited HtNSCs by activating integrated stress response signaling. This consequently hinders the repair of damaged neurons by inhibiting HtNSC proliferation and differentiation. Overall, our findings underscore the pivotal role of the integrated stress response pathway in AT-induced HtNSC senescence and hypothalamic damage. Additionally, the present study offers novel perspectives to understand the mechanisms of AT-induced neurotoxicity and provides preliminary evidence linking AT contamination to the development of NDs.

Cerebral palsy (CP) is the most common physical disability in children, yet lacks an ideal animal model or effective treatment. This study aimed to develop a reliable CP model in neonatal rats and explore the effectiveness and underlying mechanisms of human neural stem cells (hNSCs) transplantation during the sequelae phase of CP.

Vasoconstrictor endothelin-1 (ET-1) was administered intracranially to the motor cortex and striatum of rats on postnatal day 5 to establish a CP model. hNSCs (5 × 105/5 μL) pretreated with hypoxia (5% O2 for 24 h) were transplanted near the infarct 3 weeks after ET-1 injury (the sequelae phase). The distribution and differentiation of hNSCs were observed after transplantation. Changes in neurotrophic factors, neurogenesis, angiogenesis, axonal plasticity, and motor function were analyzed.

Neurobehavioral tests showed poor muscle strength and postural control in young ET-1 rats. Motor deficits of the left forelimb and gait abnormalities persisted into adulthood. Histopathological findings and MRI indicated the atrophy of the cortex, striatum, and adjacent corpus callosum in ET-1 rats. At 56 days after transplantation, hNSCs were widely distributed in the ipsilateral hemisphere, and differentiated into neurons, oligodendrocytes and astrocytes. Transplantation of hNSCs increased BDNF and VEGF expression, EdU+ cell number in the SVZ area, RECA-1+ vessel density and GAP-43 intensity around the lesion in ET-1 rats. The cylinder test revealed a significant increase in the left forelimb motor function from 28 days after transplantation, and the staircase and CatWalk tests showed improvements in fine motor function and gait parameters.

Intracerebral injection of ET-1 modelled key functional and histopathological features of CP. hNSCs transplanted during the sequelae phase of CP resulted in long-term improvement in motor performance, possibly attributed to its capacity to stimulate neurotrophic factors, facilitate neurogenesis, angiogenesis, and promote axonal plasticity.

Atrazine, a widely used herbicide, has become a major pollutant in agricultural water bodies. Pesticide contamination, including atrazine, is linked to a high incidence of age-related neurodegenerative diseases, suggesting its neurotoxic potential. Lycopene, a potent antioxidant, is renowned for its diverse pharmacological effects, especially its neuroprotective properties. However, the underlying pharmacological mechanisms of lycopene and its impact on potential pathways against atrazine-induced hypothalamic damage have not been elucidated.

Our study aimed to elucidate how lycopene ameliorates hypothalamic injury triggered by atrazine exposure, with a special focus on the pluripotency of neural stem cells (NSCs) and pathways involved in cell senescence.

Mice were administered lycopene and/or atrazine via gavage for 21 days. The C17.2 NSC cell line and specific molecular inhibitors were utilized to examine the potential protective effects of lycopene in vitro. Morphological changes and ultrastructural damage in the hypothalamus were observed by hematoxylin-eosin staining and transmission electron microscopy, respectively. The mechanisms of action of lycopene were explored through various methods, including senescence β-galactosidase staining, multiplex immunofluorescence, Western blotting and qRT‒PCR.

Our results indicated that lycopene notably ameliorated atrazine-induced histological and ultrastructural damage, as well as the loss of intact and mature neurons in mouse hypothalami. Additionally, hypothalamic NSCs (HtNSCs) and microglia were recruited to areas of neuronal injury after atrazine exposure; intriguingly, lycopene treatment reduced this recruitment. Through in vivo and in vitro assays, we elucidated the outcomes of atrazine-induced HtNSC recruitment and neuronal loss, along with the neuroprotective mechanisms of lycopene. Mechanistically, lycopene prevents atrazine-induced senescence in HtNSCs and enhances their proliferation and differentiation by inhibiting the integrated stress response (ISR) signaling pathway, thus promoting the renewal of damaged neurons in the hypothalamus.

Collectively, the results of the present study reveal, for the first time, that lycopene mitigates atrazine-induced HtNSC senescence by modulating the ISR signaling pathway. These findings offer novel insights into the role of lycopene in preventing and alleviating NSC senescence and suggest its potential development as a new therapy for neurodegenerative diseases.

Alzheimer's disease was induced in female Wistar rats by bilateral injection of β-amyloid fragment 1-42 into the hippocampal region. After 8 weeks, ensheathing cells of the olfactory mucosa were transplanted into the hippocampus at the same stereotactic coordinates. These cells survived for 8 weeks; large clusters of cells were observed on week 4. On weeks 3-5 after transplantation of ensheathing cells, experimental animals demonstrated a significant cognitive improvement (memory and spatial orientation). The obtained results create prerequisites for further studies of ensheathing cells as a potential cell product for personalized therapy of Alzheimer's disease.

Ischemic stroke induces adult neurogenesis in the subventricular zone (SVZ), even in elderly patients. Harnessing of this neuroregenerative response presents the therapeutic potential for post-stroke recovery. We found that phenylethanoid glycosides (PhGs) derived from Cistanche deserticola aid neural repair after stroke by promoting neurogenesis. Among these, 2-acetylacteoside had the most potent on the proliferation of neural stem cells (NSCs) in vitro. Furthermore, 2-acetylacteoside was shown to alleviate neural dysfunction by increase neurogenesis both in vivo and in vitro. RNA-sequencing analysis highlighted differentially expressed genes within the PI3K/Akt signaling pathway. The candidate target Akt was validated as being regulated by 2-acetylacteoside, which, in turn, enhanced the proliferation and differentiation of cultured NSCs after oxygen-glucose deprivation/reoxygenation (OGD/R), as evidenced by Western blot analysis. Subsequent analysis using cultured NSCs from adult subventricular zones (SVZ) confirmed that 2-acetylacteoside enhanced the expression of phosphorylated Akt (p-Akt), and its effect on NSC neurogenesis was shown to be dependent on the PI3K/Akt pathway. In summary, our findings elucidate for the first time the role of 2-acetylacteoside in enhancing neurological recovery, primarily by promoting neurogenesis via Akt activation following ischemic brain injury, which offers a novel strategy for long-term cerebrological recovery in ischemic stroke.

Calculus Bovis (C. bovis) is a precious traditional Chinese medicine of animal origin, and it is one of the traditional medicines for treating cerebral inflammatory diseases such as stroke. However, the pharmacological action of C. bovis on ischemic stroke (IS) and its mechanism are still unclear. The purpose of this study was to investigate the potential mechanism to treat IS. Chemical constituents of different varieties of C. bovis were analyzed and confirmed by HPLC-MS/MS technique. We constructed a component and corresponding target network and drug-disease target protein-protein interaction (PPI) network. GO and KEGG enrichment analysis were performed. The molecular docking of the main compound with the target protein. Subsequently, the potential mechanism of therapy for IS was verified in vivo by zebrafish model. We introduced Raman spectroscopy to detect changes in the biochemical composition of zebrafish. 13 active chemical constituents and 129 potential targets were selected. 122 KEGG signaling pathways were obtained. The binding energy of the main compounds is less than -4.5. The results of animal experiments showed that C. bovis could significantly improve Ponatinib-induced IS, decrease the aggregation degree of brain macrophages, reduce the number of macrophage migrations, and significantly increase the expression level of NR3C1. Raman information indicated that the biochemical composition in the brain of the Ponatinib-induced group shifted to the control group. The mechanism may be related to anti-inflammatory process and regulation of lipid metabolism. This study demonstrates that Raman spectroscopy has great potential as a drug evaluation tool in living larval zebrafish.

Hypoxic-ischemic encephalopathy (HIE) is a major cause of neonatal disability and mortality. Although intensive studies and therapeutic approaches, there are limited restorative treatments till now. Human embryonic stem cell (hESCs)-derived cortical neural progenitors have shown great potentials in ischemic stroke in adult brain. However, it is unclear whether they are feasible for cortical reconstruction in immature brain with hypoxic-ischemic encephalopathy.

By using embryonic body (EB) neural differentiation method combined with DAPT pre-treatment and quantitative cell transplantation, human cortical neuroblasts were obtained and transplanted into the cortex of hypoxic-ischemic injured brain with different dosages 2 weeks after surgery. Then, immunostaining, whole-cell patch clamp recordings and behavioral testing were applied to explore the graft survival and proliferation, fate commitment of cortical neuroblasts in vitro, neural circuit reconstruction and the therapeutic effects of cortical neuroblasts in HIE brain.

Transplantation of human cortical neural progenitor cells (hCNPs) in HIE-injured cortex exhibited long-term graft overgrowth. DAPT pre-treatment successfully synchronized hCNPs from different developmental stages (day 17, day 21, day 28) to deep layer cortical neuroblasts which survived well in HIE injured brain and greatly prevented graft overgrowth after transplantation. Importantly, the cortical neuroblasts primarily differentiated into deep-layer cortical neurons and extended long axons to their projection targets, such as the cortex, striatum, thalamus, and internal capsule in both ipsilateral and contralateral HIE-injured brain. The transplanted cortical neurons established synapses with host cortical neurons and exhibited spontaneous excitatory or inhibitory post-synaptic currents (sEPSCs or sIPSCs) five months post-transplantation. Rotarod and open field tests showed greatly improved animal behavior by intra-cortex transplantation of deep layer cortical neuroblasts in HIE injured brain.

Transplanted hESCs derived cortical neuroblasts survive, project to endogenous targets, and integrate into host cortical neural circuits to rescue animal behavior in the HIE-injured brain without graft overgrowth, providing a novel and safe cell replacement strategy for the future treatment of HIE.

JOURNAL/nrgr/04.03/01300535-202410000-00025/figure1/v/2024-02-06T055622Z/r/image-tiff In situ direct reprogramming technology can directly convert endogenous glial cells into functional neurons in vivo for central nervous system repair. Polypyrimidine tract-binding protein 1 (PTB) knockdown has been shown to reprogram astrocytes to functional neurons in situ. In this study, we used AAV-PHP.eB-GFAP-shPTB to knockdown PTB in a mouse model of ischemic stroke induced by endothelin-1, and investigated the effects of GFAP-shPTB-mediated direct reprogramming to neurons. Our results showed that in the mouse model of ischemic stroke, PTB knockdown effectively reprogrammed GFAP-positive cells to neurons in ischemic foci, restored neural tissue structure, reduced inflammatory response, and improved behavioral function. These findings validate the effectiveness of in situ transdifferentiation of astrocytes, and suggest that the approach may be a promising strategy for stroke treatment.

Oxidative stress is widely involved in the pathological process of ischemic stroke and ischemia-reperfusion. Several research have demonstrated that eliminating or reducing oxidative stress can alleviate the pathological changes of ischemic stroke. However, current clinical antioxidant treatment did not always perform as expected. This bibliometric research aims to identify research trends, topics, hotspots, and evolution on oxidative stress in the field of ischemic stroke, and to find potentially antioxidant strategies in future clinical treatment. Relevant publications were searched from the Web of Science (WOS) Core Collection databases (2001-2022). VOSviewer was used to visualize and analyze the development trends and hotspots. In the field of oxidative stress and ischemic stroke, the number of publications increased significantly from 2001 to 2022. China and the USA were the leading countries for publication output. The most prolific institutions were Stanford University. Journal of Cerebral Blood Flow and Metabolism and Stroke were the most cited journals. The research topics in this field include inflammation with oxidative stress, mitochondrial damage with oxidative stress, oxidative stress in reperfusion injury, oxidative stress in cognitive impairment and basic research and clinical translation of oxidative stress. Moreover, "NLRP3 inflammasome," "autophagy," "mitophagy," "miRNA," "ferroptosis," and "signaling pathway" are the emerging research hotspots in recent years. At present, multi-target regulation focusing on multi-mechanism crosstalk has progressed across this period, while challenges come from the transformation of basic research to clinical application. New detection technology and new nanomaterials are expected to integrate oxidative stress into the clinical treatment of ischemic stroke better.

Pre-clinical trials have demonstrated the neuroprotective effects of transplanted human neural stem cells (hNSCs) during the post-ischemic phase. However, the exact neuroprotective mechanism remains unclear. Tunneling nanotubes (TNTs) are long plasma membrane bridges that physically connect distant cells, enabling the intercellular transfer of mitochondria and contributing to post-ischemic repair processes. Whether hNSCs communicate through TNTs and their role in post-ischemic neuroprotection remains unknown. In this study, non-immortalized hNSC lines derived from fetal human brain tissues were examined to explore these possibilities and assess the post-ischemic neuroprotection potential of these hNSCs. Using Tau-STED super-resolution confocal microscopy, live cell time-lapse fluorescence microscopy, electron microscopy, and direct or non-contact homotypic co-cultures, we demonstrated that hNSCs generate nestin-positive TNTs in both 3D neurospheres and 2D cultures, through which they transfer functional mitochondria. Co-culturing hNSCs with differentiated SH-SY5Y (dSH-SY5Y) revealed heterotypic TNTs allowing mitochondrial transfer from hNSCs to dSH-SY5Y. To investigate the role of heterotypic TNTs in post-ischemic neuroprotection, dSH-SY5Y were subjected to oxygen-glucose deprivation (OGD) followed by reoxygenation (OGD/R) with or without hNSCs in direct or non-contact co-cultures. Compared to normoxia, OGD/R dSH-SY5Y became apoptotic with impaired electrical activity. When OGD/R dSH-SY5Y were co-cultured in direct contact with hNSCs, heterotypic TNTs enabled the transfer of functional mitochondria from hNSCs to OGD/R dSH-SY5Y, rescuing them from apoptosis and restoring the bioelectrical profile toward normoxic dSH-SY5Y. This complete neuroprotection did not occur in the non-contact co-culture. In summary, our data reveal the presence of a functional TNTs network containing nestin within hNSCs, demonstrate the involvement of TNTs in post-ischemic neuroprotection mediated by hNSCs, and highlight the strong efficacy of our hNSC lines in post-ischemic neuroprotection. Human neural stem cells (hNSCs) communicate with each other and rescue ischemic neurons through nestin-positive tunneling nanotubes (TNTs). A Functional mitochondria are exchanged via TNTs between hNSCs. B hNSCs transfer functional mitochondria to ischemic neurons through TNTs, rescuing neurons from ischemia/reperfusion ROS-dependent apoptosis.

Stem cell transplantation is a potential therapeutic strategy for ischemic stroke. However, despite many years of preclinical research, the application of stem cells is still limited to the clinical trial stage. Although stem cell therapy can be highly beneficial in promoting functional recovery, the precise mechanisms of action that are responsible for this effect have yet to be fully elucidated. Omics analysis provides us with a new perspective to investigate the physiological mechanisms and multiple functions of stem cells in ischemic stroke. Transcriptomic, proteomic, and metabolomic analyses have become important tools for discovering biomarkers and analyzing molecular changes under pathological conditions. Omics analysis could help us to identify new pathways mediated by stem cells for the treatment of ischemic stroke via stem cell therapy, thereby facilitating the translation of stem cell therapies into clinical use. In this review, we summarize the pathophysiology of ischemic stroke and discuss recent progress in the development of stem cell therapies for the treatment of ischemic stroke by applying multi-level omics. We also discuss changes in RNAs, proteins, and metabolites in the cerebral tissues and body fluids under stroke conditions and following stem cell treatment, and summarize the regulatory factors that play a key role in stem cell therapy. The exploration of stem cell therapy at the molecular level will facilitate the clinical application of stem cells and provide new treatment possibilities for the complete recovery of neurological function in patients with ischemic stroke.

Nerve injury can not only lead to sensory and motor dysfunction, but also be complicated with neuropathic pain (NPP), which brings great psychosomatic injury to patients. At present, there is no effective treatment for NPP. Based on the functional characteristics of cell transplantation in nerve regeneration and injury repair, cell therapy has been used in the exploratory treatment of NPP and has become a promising treatment of NPP. In this article, we discuss the current mainstream cell types for the treatment of NPP, including Schwann cells, olfactory ensheathing cells, neural stem cells and mesenchymal stem cells in the treatment of NPP. These bioactive cells transplanted into the host have pharmacological properties of decreasing pain threshold and relieving NPP by exerting nutritional support, neuroprotection, immune regulation, promoting axonal regeneration, and remyelination. Cell transplantation can also change the microenvironment around the nerve injury, which is conducive to the survival of neurons. It can effectively relieve pain by repairing the injured nerve and rebuilding the nerve function. At present, some preclinical and clinical studies have shown that some encouraging results have been achieved in NPP treatment based on cell transplantation. Therefore, we discussed the feasible strategy of cell transplantation as a treatment of NPP and the problems and challenges that need to be solved in the current application of cell transplantation in NPP therapy.

Neonatal hypoxic-ischemic encephalopathy (HIE) is a critical condition characterized by significant brain damage due to insufficient blood flow and oxygen delivery at birth, leading to high rates of neonatal mortality and long-term neurological deficits worldwide. 2,3-Diphosphoglyceric acid (2,3-DPG), a small molecule metabolite prevalent in erythrocytes, plays an important role in regulating oxygen delivery, but its potential neuroprotective role in hypoxic-ischemic brain damage (HIBD) has yet to be fully elucidated. Our research reveals that the administration of 2,3-DPG effectively reduces neuron damage caused by hypoxia-ischemia (HI) both in vitro and in vivo. We observed a notable decrease in HI-induced neuronal cell apoptosis, attributed to the downregulation of Bax and cleaved-caspase 3, alongside an upregulation of Bcl-2 expression. Furthermore, 2,3-DPG significantly alleviates oxidative stress and mitochondrial damage induced by oxygen-glucose deprivation/reperfusion (OGD/R). The administration of 2,3-DPG in rats subjected to HIBD resulted in a marked reduction in brain edema and infarct volume, achieved through the suppression of neuronal apoptosis and neuroinflammation. Using RNA-seq analysis, we validated that 2,3-DPG offers protection against neuronal apoptosis under HI conditions by modulating the p38 MAPK pathway. These insights indicated that 2,3-DPG might act as a promising novel therapeutic candidate for HIE.

JOURNAL/nrgr/04.03/01300535-202408000-00031/figure1/v/2023-12-16T180322Z/r/image-tiff Proliferation of neural stem cells is crucial for promoting neuronal regeneration and repairing cerebral infarction damage. Transcranial magnetic stimulation (TMS) has recently emerged as a tool for inducing endogenous neural stem cell regeneration, but its underlying mechanisms remain unclear. In this study, we found that repetitive TMS effectively promotes the proliferation of oxygen-glucose deprived neural stem cells. Additionally, repetitive TMS reduced the volume of cerebral infarction in a rat model of ischemic stroke caused by middle cerebral artery occlusion, improved rat cognitive function, and promoted the proliferation of neural stem cells in the ischemic penumbra. RNA-sequencing found that repetitive TMS activated the Wnt signaling pathway in the ischemic penumbra of rats with cerebral ischemia. Furthermore, PCR analysis revealed that repetitive TMS promoted AKT phosphorylation, leading to an increase in mRNA levels of cell cycle-related proteins such as Cdk2 and Cdk4. This effect was also associated with activation of the glycogen synthase kinase 3β/β-catenin signaling pathway, which ultimately promotes the proliferation of neural stem cells. Subsequently, we validated the effect of repetitive TMS on AKT phosphorylation. We found that repetitive TMS promoted Ca2+ influx into neural stem cells by activating the P2 calcium channel/calmodulin pathway, thereby promoting AKT phosphorylation and activating the glycogen synthase kinase 3β/β-catenin pathway. These findings indicate that repetitive TMS can promote the proliferation of endogenous neural stem cells through a Ca2+ influx-dependent phosphorylated AKT/glycogen synthase kinase 3β/β-catenin signaling pathway. This study has produced pioneering results on the intrinsic mechanism of repetitive TMS to promote neural function recovery after ischemic stroke. These results provide a strong scientific foundation for the clinical application of repetitive TMS. Moreover, repetitive TMS treatment may not only be an efficient and potential approach to support neurogenesis for further therapeutic applications, but also provide an effective platform for the expansion of neural stem cells.

Pyroptosis, inflammation-related programed cell death mediated by NLRP3 inflammasome, is involved in the pathogenesis of cerebral hypoxic-ischemic injury. Our study aims to explore the biological role of growth differentiation factor (GDF)15 in oxygen-glucose deprivation/reoxygenation (OGD/R)-induced neuronal pyroptosis.

HT22 neurons were subjected to OGD/R to simulate cerebral hypoxic-ischemic injury. Cells were transfected with plasmids to overexpress GDF15, or lentiviral-based shRNAs constructs to silence GDF15. ELISA assay was used to detect GDF15, IL-1β, IL-18, and neuron specific enolase (NSE) levels. Cell pyroptosis was measured by flow cytometery. Chromatin immunoprecipitation assay was used to detect interaction of H3K27ac with GDF15 promoter. GDF15, NLRP3, Caspase-1 p20 and GSDMD-N expressions were measured by Western blotting.

Patients with malignant middle cerebral artery infarction showed decreased GDF15, but increased IL-1β, IL-18, and NSE levels in serum compared to healthy controls. OGD/R treatment caused significant increases in the levels of IL-1β, IL-18 and NSE, percentages of pyroptotic cells, and expressions of NLRP3, Caspase-1 p20, and GSDMD in HT22 cells, which were markedly reversed by GDF15 overexpression. However, GDF15 knockdown resulted in neuronal injury similar to those observed in OGD/R treatment. The GDF15 knockdown-induced effects were counteracted by treatment with NLRP3 inhibitor. OGD/R decreased the enrichment of H3K27ac in the promoter of GDF15 to down-regulate GDF15, but was compromised by co-treatment with HDAC2 inhibitor.

Our data demonstrates that GDF15 attenuates OGD/R-induced pyroptosis through NLRP3 inflammasome. HDAC2 is involved in mediating OGD-induced GDF15 down-regulation via H3K27ac modification. GDF15 overexpression and HDAC2 inhibition hold potential as useful therapeutic strategies for neuroprotection.

Ischemic stroke, a cerebrovascular disease caused by arterial occlusion in the brain, can lead to brain impairment and even death. Stem cell therapies have shown positive advantages to treat ischemic stroke because of their extended time window, but the cell viability is poor when transplanted into the brain directly. Therefore, a new hydrogel GelMA-T was developed by introducing taurine on GelMA to transplant neural stem cells. The GelMA-T displayed the desired photocuring ability, micropore structure, and cytocompatibility. Its compressive modulus was more similar to neural tissue compared to that of GelMA. The GelMA-T could protect SH-SY5Y cells from injury induced by OGD/R. Furthermore, the NE-4C cells showed better proliferation performance in GelMA-T than that in GelMA during both 2D and 3D cultures. All results demonstrate that GelMA-T possesses a neuroprotective effect for ischemia/reperfusion injury against ischemic stroke and plays a positive role in promoting NSC proliferation. The novel hydrogel is anticipated to function as cell vehicles for the transplantation of neural stem cells into the stroke cavity, aiming to treat ischemic stroke.

The aim of this study was to identify related scientific outputs and emerging topics of stem cells in neonatal hypoxic-ischemic encephalopathy (NHIE) and cerebral palsy (CP) through bibliometrics and literature review. All relevant publications on stem cell therapy for NHIE and CP were screened from websites and analyzed research trends. VOSviewer and CiteSpace were applied to visualize and quantitatively analyze the published literature to provide objective presentation and prediction. In addition, the clinical trials, published articles, and projects of the National Natural Science Foundation of China associated with stem cell therapy for NHIE and CP were summarized. A total of 294 publications were associated with stem cell therapy for NHIE and CP. Most publications and citations came from the USA and China. Monash University and University Medical Center Utrecht produced the most publications. Pediatric research published the most studies on stem cell therapy for NHIE and CP. Heijnen C and Kavelaars A published the most articles. Cluster analyses show that current research trend is more inclined toward the repair mechanism and clinical translation of stem cell therapy for NHIE and CP. By summarizing various studies of stem cells in NHIE and CP, it is indicated that this research direction is a hot topic at present. Furthermore, organoid transplantation, as an emerging and new therapeutic approach, brings new hope for the treatment of NHIE and CP. This study comprehensively summarized and analyzed the research trend of global stem cell therapy for NHIE and CP. It has shown a marked increase in stem cell therapy for NHIE and CP research. In the future, more efforts will be made on exploring stem cell or organoid therapy for NHIE and CP and more valuable related mechanisms of action to achieve clinical translation as soon as possible.

Acidic postconditioning by transient CO2 inhalation applied within minutes after reperfusion has neuroprotective effects in the acute phase of stroke. However, the effects of delayed chronic acidic postconditioning (DCAPC) initiated during the subacute phase of stroke or other acute brain injuries are unknown. Mice received daily DCAPC by inhaling 5%/10%/20% CO2 for various durations (three cycles of 10- or 20-min CO2 inhalation/10-min break) at days 3-7, 7-21, or 3-21 after photothrombotic stroke. Grid-walk, cylinder, and gait tests were used to assess motor function. DCAPC with all CO2 concentrations significantly promoted motor functional recovery, even when DCAPC was delayed for 3-7 days. DCAPC enhanced the puncta density of GAP-43 (a marker of axon growth and regeneration) and synaptophysin (a marker of synaptogenesis) and reduced the amoeboid microglia number, glial scar thickness and mRNA expression of CD16 and CD32 (markers of proinflammatory M1 microglia) compared with those of the stroke group. Cerebral blood flow (CBF) increased in response to DCAPC. Furthermore, the mRNA expression of TDAG8 (a proton-activated G-protein-coupled receptor) was increased during the subacute phase of stroke, while DCAPC effects were blocked by systemic knockout of TDAG8, except for those on CBF. DCAPC reproduced the benefits by re-expressing TDAG8 in the peri-infarct cortex of TDAG8-/- mice infected with HBAAV2/9-CMV-TDAG8-3flag-ZsGreen. Taken together, we first showed that DCAPC promoted functional recovery and brain tissue repair after stroke with a wide therapeutic time window of at least 7 days after stroke. Brain-derived TDAG8 is a direct target of DCAPC that induces neuroreparative effects.

Ischemic stroke, being a prominent contributor to global disability and mortality, lacks an efficacious therapeutic approach in current clinical settings. Neural stem cells (NSCs) are a type of stem cell that are only found inside the nervous system. These cells can differentiate into various kinds of cells, potentially regenerating or restoring neural networks within areas of the brain that have been destroyed. This review begins by providing an introduction to the existing therapeutic approaches for ischemic stroke, followed by an examination of the promise and limits associated with the utilization of NSCs for the treatment of ischemic stroke. Subsequently, a comprehensive overview was conducted to synthesize the existing literature on the underlying processes of neural stem cell-derived small extracellular vesicles (NSC-sEVs) transplantation therapy in the context of ischemic stroke. These mechanisms encompass neuroprotection, inflammatory response suppression, and endogenous nerve and vascular regeneration facilitation. Nevertheless, the clinical translation of NSC-sEVs is hindered by challenges such as inadequate targeting efficacy and insufficient content loading. In light of these limitations, we have compiled an overview of the advancements in utilizing modified NSC-sEVs for treating ischemic stroke based on current methods of extracellular vesicle modification. In conclusion, examining NSC-sEVs-based therapeutic approaches is anticipated to be prominent in both fundamental and applied investigations about ischemic stroke.

The central role of the brain in governing systemic functions within human physiology underscores its paramount significance as the focal point of physiological regulation. The brain, a highly sophisticated organ, orchestrates a diverse array of physiological processes encompassing motor control, sensory perception, cognition, emotion, and the regulation of vital functions, such as heartbeat, respiration, and hormonal equilibrium. A notable attribute of neurological diseases manifests as the depletion of neurons and the occurrence of tissue necrosis subsequent to injury. The transplantation of neural stem cells (NSCs) into the brain exhibits the potential for the replacement of lost neurons and the reconstruction of neural circuits. Furthermore, the transplantation of other types of cells in alternative locations can secrete nutritional factors that indirectly contribute to the restoration of nervous system equilibrium and the mitigation of neural inflammation. This review summarized a comprehensive investigation into the role of NSCs, hematopoietic stem cells, mesenchymal stem cells, and support cells like astrocytes and microglia in alleviating neurological deficits after cell infusion. Moreover, a thorough assessment was undertaken to discuss extant constraints in cellular transplantation therapies, concurrently delineating indispensable model-based methodologies, specifically on organoids, which were essential for guiding prospective research initiatives in this specialized field.

Ischemia-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.

NSCs 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.

Overall 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.

The 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.

Ischemic stroke is a leading cause of disability and death. Current treatments are limited. Stem cell therapy has been highlighted as a potentially effective treatment to mitigate damage and restore function, but efficacy results are mixed. This study aimed to systematically review the literature on stem cell therapies for early acute ischemic stroke; and identify opportunities for future research to facilitate the development of an effective stem cell-based treatment. Original research published within the last 10 years that focused on the evaluation of a stem cell-based treatment for acute ischemic stroke in adult patients or subjects was included. Risk of bias was assessed using the SYRCLE and Cochrane risk of bias tools for animal and human studies, respectively. 3,396 articles were screened, 58 full-text articles were reviewed and 33 met inclusion criteria. Many studies appeared to be at risk of bias. Study designs and results were heterogeneous. Most studies were preclinical and involved stem cell administration within 24 hours. Seven studies tested the effects of multiple administration timepoints and one investigated repeat dosing. Six studies were conducted in humans and stem cell administration ranged from 24 hours to 90 days post stroke. Most studies employed the use of mesenchymal stem cells. The most appropriate cell delivery method appeared to be intra-arterial. Evidence suggests that stem cell therapy may be associated with beneficial effects. A literature gap analysis identified numerous opportunities for treatment development.

Traumatic brain injury (TBI) is the main cause of disability, mental health disorder, and even death, with its incidence and social costs rising steadily. Although different treatment strategies have been developed and tested to mitigate neurological decline, a definitive cure for these conditions remains elusive. Studies have revealed that various neurotrophins represented by the brain-derived neurotrophic factor are the key regulators of neuroinflammation, apoptosis, blood-brain barrier permeability, neurite regeneration, and memory function. These factors are instrumental in alleviating neuroinflammation and promoting neuroregeneration. In addition, neural stem cells (NSC) contribute to nerve repair through inherent neuroprotective and immunomodulatory properties, the release of neurotrophins, the activation of endogenous NSCs, and intercellular signaling. Notably, innovative research proposals are emerging to combine BDNF and NSCs, enabling them to synergistically complement and promote each other in facilitating injury repair and improving neuron differentiation after TBI. In this review, we summarize the mechanism of neurotrophins in promoting neurogenesis and restoring neural function after TBI, comprehensively explore the potential therapeutic effects of various neurotrophins in basic research on TBI, and investigate their interaction with NSCs. This endeavor aims to provide a valuable insight into the clinical treatment and transformation of neurotrophins in TBI, thereby promoting the progress of TBI therapeutics.