Search Results (316)

Neurogenesis is tightly regulated by complex interactions among neural stem and progenitor cells (NSCs/NPCs), blood vessels, microglia, and extracellular matrix components within the neurogenic niche. In the embryonic brain, NSCs reside along the ventricular surface, where cerebrospinal fluid (CSF) directly regulates their proliferation. Here, we identify Akhirin (AKH) as a critical regulator that preserves the integrity of the NSC niche during mouse brain development. At embryonic day 14.5, AKH is secreted and enriched at the apical surface of choroid plexus epithelial cells and the ventricular lining. Loss of AKH leads to increases the inflammatory cytokine expression in the CSF and disrupts NSC niche homeostasis. Furthermore, AKH is cleaved upon inflammatory stimulation, and its LCCL domain directly binds bacteria, thereby preventing their spread. These findings reveal that AKH functions as a protective barrier molecule within the developing neurogenic niche, providing immune protection and preserving NSC niche homeostasis during periods when the innate immune defenses are still immature. Full article

Background: Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease of the central nervous system (CNS), characterised by inflammation, demyelination, and progressive neurodegeneration. Although current disease-modifying therapies (DMTs) can reduce relapse rates and inflammatory activity, they rarely stop long-term progression or repair neurological damage. In recent years, cell-based therapies have emerged as promising approaches to promote immune regulation and neuroregeneration in MS. Methods: This review summarises the current clinical evidence from studies in humans investigating cell-based treatments for MS, including autologous haematopoietic stem cell transplantation (AHSCT), mesenchymal stem cells (MSCs), and neural stem or progenitor cells (NSCs). A systematic literature search was performed using PubMed, Scopus, and ClinicalTrials.gov, focusing on human clinical trials that met specific inclusion criteria. Results: Prevailing findings show that AHSCT provides the most consistent benefit, achieving long-term immune reconstitution and remission in patients with highly active relapsing–remitting MS (RRMS), although it carries procedural risks. MSC therapies have demonstrated good safety and biological activity, especially when delivered intrathecally (IT) in progressive MS, though clinical results remain variable. Conclusions: NSC-based treatments are still at an early stage of clinical research but show potential for CNS repair. The main limitations across studies include differences in protocols, small sample sizes, and short follow-up periods. Further large-scale, randomised controlled trials are needed to confirm long-term efficacy, define optimal delivery methods, and establish standardised clinical protocols. Full article

Neuroinflammation is a key response to disturbed CNS homeostasis, largely mediated by activated microglia, and excessive microglia-driven inflammation can negatively impact neurogenesis. ZEB1 plays a crucial role in neurogenesis and brain development by influencing neural stem cell (NSC) maintenance, proliferation, and differentiation. This study aimed to evaluate how the knockdown of ZEB1 influences the behavior of NSCs in inflammatory environments. NSCs were isolated from the subventricular zone of rats, and ZEB1 knockdown was achieved using ZEB1 siRNA. A conditioned medium derived from lipopolysaccharide-activated microglia was utilized to induce inflammatory responses in NSCs. The silencing of ZEB1 in NSCs significantly reduced the expression of ZEB1. Furthermore, ZEB1 knockdown in NSCs resulted in a significant decrease in neurosphere formation, cell migration ability, reactive oxygen species generation, and various cytokine levels under both non-inflammatory and inflammatory conditions. These findings reveal the regulatory role of ZEB1 in the modulation of NSC behavior, suggesting that targeting ZEB1 may provide a potential therapeutic strategy for neuroinflammatory CNS disorders. Full article

While significant progress has been made in understanding the heterogeneity of Neural Stem Cells (NSCs), our understanding of similar heterogeneity among the more abundant transit amplifying progenitors is lagging. Our work on the neural progenitors (NPs) of the neonatal subventricular zone (SVZ) began over a decade ago, when we used antibodies to the four antigens, CD133, LeX, CD140a, and NG2 to perform Fluorescence-activated cell sorting to classify subsets of the neonatal mouse SVZ as either multi-potential (MP1, MP2, MP3, MP4 and PFMPs), glial-restricted (GRP1, GRP2, and GRP3), or neuron-astrocyte restricted (BNAP). Using RNA sequencing, we have characterized the distinctive molecular fingerprints of four SVZ neural progenitor subtypes and compared their gene expression profiles to those of the NSCs. We performed bioinformatic analyses to provide insights into each NP type’s unique interactome and the transcription factors regulating their development. Overall, we identified 1581 genes upregulated in at least one NP subset compared to the NSCs. Of these genes, 796 genes were upregulated in BNAP/GRP1 compared to NSCs; 653 in GRP2/MP3; 440 in GRP3; and 527 in PFMPs. One gene that emerged from our analysis that can be used to distinguish the NPs from the NSCs is Etv1, also known as Er81. Also notable is that the NSCs downregulated cilia formation genes as they differentiated to become multipotential progenitors. Among the NPs, both PFMP and GRP3 subtypes differentially expressed genes related to neuron and oligodendrocyte development, including Matn4, Lhfpl3 and Olig2. GRP3s uniquely expressed Etv5, a transcription factor known to promote glial cell fate specification, while PFMPs uniquely expressed Lhx6, a transcription factor that regulates interneuron specification. PFMPs also expressed transcripts for olfactory receptors. Unlike the other NPs, the GRP1 and GRP2 NPs upregulated expression of genes for proteins involved in immune function. The present work will serve as an important resource for investigators interested in further defining the transit amplifying progenitors of the mammalian SVZ. Full article

Organophosphate (OP) and carbamate pesticides are widely employed in agriculture to facilitate the production of economically viable crops. However, pesticide contamination of food, water, and air leads to undesired human exposure. Neuronal tissue may be particularly vulnerable to pesticide toxicity during periods of neurodevelopment. Hence, this study aimed to investigate the neurotoxicity of three pesticide compounds, namely chlorpyrifos-oxon (CPO), azamethiphos (AZO), and aldicarb, on human neural progenitor cells (hNPCs) and whether toxicity differed between undifferentiated and differentiated stem cells. Undifferentiated and differentiated hNPCs were exposed to these neurotoxicants at concentrations of 0–200 µM for 24 h, and cell viability was evaluated using 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. The impact of the neurotoxicants on cellular bioenergetics was determined by quantifying cellular ATP levels and the production of reactive oxygen species (ROS) using a 2′,7′-dichlorofluorescein diacetate (DCFDA) assay. Concentration–response curves were also generated to measure their relative inhibition of AChE. The neurotoxicants induced concentration-dependent reductions in cell viability (p < 0.0001), cellular ATP levels (p < 0.0001), and the inhibition of AChE (p < 0.0001). Notably, differentiated neurons displayed higher sensitivity than undifferentiated neural stem cells (NSCs), with a toxicity threshold of ≥1 µM. ROS levels were significantly increased (p < 0.0001) following neurotoxicant exposures, more so in differentiated cells, with levels that correlated with cytotoxicity, cell death, and the induction of oxidatively damaged proteins in surviving cells. These findings suggest a central role of oxidative stress and protein oxidation in mediating the neurotoxic effects of pesticide compounds on NSCs. Furthermore, the heightened susceptibility of NSCs to pesticide toxicity after differentiation is indicative of human vulnerability during periods of neurodevelopment. Full article

Cellular transplantation therapies have been extensively used in experimental spinal cord injury research. However, there is no consensus as to what the most effective cellular controls for the therapeutic cell of interest are. For this reason, we examined whether dead cells obtained through prolonged heat treatment can act as an appropriate cellular control for intravenously injected Sca-1+ mesenchymal precursor cells (MPCs) in C5 unilateral contusion cervical spinal cord injury. This was tested in single intravenous MPC injection alone or intravenous MPC plus intraspinal neural stem cell (NSC) combinatory transplantation studies. MPCs were isolated from the compact bone of FVB mice, while NSCs were isolated from the subventricular zone of luciferase–GFP transgenic FVB mice. Dead MPCs were obtained by heating at 72 °C for at least 12 h. In the MPC only transplant study, injured mice received an injection of 1 × 10⁶ dead or live MPCs D1 post-injury. Mice were then sacrificed at 8 weeks post-injury. In this study, intravenous injections of dead MPCs showed no statistical difference in injured paw usage compared to live MPCs, but behavior was improved compared to the media-vehicle-only control at D7 and D21. In the combinatory MPC plus NSC transplant study, injured mice received an intravenous injection of 1 × 10⁶ dead or live MPCs D1 post-injury followed by intraspinal injection of 100,000 NSCs at D3 or D7 post-injury. Another two cohorts of mice received only NSCs at D3 or D7 post-injury. Mice were then sacrificed at 6 weeks post-injury. In this study, there was no functional difference in any of the groups in the dual injection study. Morphologically, mice receiving IV injection of dead MPCs had a smaller lesion size compared to the vehicular control, but the lesion size was larger than that of the lesion size in mice receiving live MPC injection. Dead cells elicited functional and anatomical benefits for the spinal-cord-injured mice. In summary, dead cells obtained through prolonged heat treatment proved to be inconsistent and not optimal for use as cellular controls for cell transplantation studies in spinal cord injury but provide positive evidence for non-transplantation-based cell therapies. Full article

Alzheimer’s disease (AD) causes progressive cognitive decline and neuronal loss, partly due to the buildup of amyloid-β (Aβ) plaques and tau tangles. Despite years of research, treatments targeting these hallmark pathologies have yielded only modest clinical success, prompting interest in regenerative approaches to restore the brain’s ability to repair itself. One such approach focuses on adult hippocampal neurogenesis, the process by which neural stem cells (NSCs) produce new neurons throughout life. In AD, this process is impaired, worsening cognitive deficits. In this review, we examine the molecular pathways that control adult neurogenesis, including transcriptional, epigenetic, inflammatory, and metabolic mechanisms, and how they become dysregulated in AD. We also highlight various therapeutic strategies aimed at boosting neurogenesis, such as pharmacological treatments, stem cell therapy, gene therapy, and epigenetic modulation. Preclinical studies indicate that enhancing neurogenesis can improve cognition and reduce brain pathology in AD models. Several of these treatments are now being tested in clinical trials. Ultimately, promoting neurogenesis may offer a promising avenue to complement current AD therapies and help restore lost neural function. Full article

Major depressive disorder (MDD) is a prevalent and disabling psychiatric condition with limited treatment options for patients who are resistant to conventional pharmacological and psychotherapeutic interventions. Stem cell (SC)-based therapies have emerged as a promising experimental approach, offering multifaceted mechanisms of action including neurogenesis, immunomodulation, antioxidative protection, and neuromodulation. This narrative review synthesizes current evidence from preclinical studies and early-phase clinical trials on the efficacy of mesenchymal stem cells (MSCs), neural stem cells (NSCs), and induced pluripotent stem cells (iPSCs) in alleviating depressive-like behaviors. Mechanistic insights include enhanced hippocampal neurogenesis, modulation of the brain-derived neurotrophic factor (BDNF)–TrkB pathway, attenuation of neuroinflammation through microglial polarization, and restoration of serotonergic signaling via peripheral-to-central pathways such as via the vagus nerve. In addition, the therapeutic potential of extracellular vesicles (EVs) and intranasal administration as non-invasive delivery strategies is discussed. While animal and first preclinical studies suggest potential benefit, significant translational barriers remain, including issues of scalability, long-term safety, and ethical considerations. Further rigorous studies are needed to validate stem-cell-based therapies as viable treatments for MDD. Full article

In this research, the proteomic landscape of 100 kDa protein extract sourced from rabbit brain was compared to extracts from liver and from organ mixture (OM). Our aim was to compare the efficacy of Nanomised Organo Peptides (NOP) ultrafiltrates from two different tissues and a tissue mixture for inducing neurite outgrowth, and subsequently to identify the molecular networks and proteins that could explain such effects. Proteins were isolated by gentle homogenization followed by crossflow ultrafiltration. Proteomic evaluation involved gel electrophoresis, complemented by mass spectrometry and bioinformatics. GO (Gene Ontology) and protein analysis of the mass spectrometry results identified a diverse array of proteins involved in critical specific biological functions, including neuronal development, regulation of growth, immune response, and lipid and metal binding. Data from this study are accessible from the ProteomeXchange repository (identifier PXD051701). Our findings highlight the presence of small proteins that play key roles in metabolic processes and biosynthetic modulation. In vitro outgrowth experiments with neural stem cells (NSCs) showed that 100 kDa protein extracts from the brain resulted in a greater increase in neurite length compared to the liver and organ mixture extracts. The protein networks identified in the NOP ultrafiltrates may significantly improve biological therapeutic strategies related to neural differentiation and outgrowth. This comprehensive proteomic analysis of 100 kDa ultrafiltrates revealed a diverse array of proteins involved in key biological processes, such as neuronal development, metabolic regulation, and immune response. Brain-specific extracts demonstrated the capacity to promote neurite outgrowth in NSCs, suggesting potential application for neuroregenerative therapies. Our findings highlight the potential of small proteins and organ-specific proteins in the development of novel targeted treatments for various diseases, particularly those related to neurodegeneration and aging. Full article

Treatment of malignant diseases using oncolytic viruses (OVs) is currently considered a promising therapeutic approach. Initial encouraging results fueled a large number of clinical trials, showcasing favorable safety profiles of OVs—but therapeutic outcomes remain far from perfect. The efficacy of systemically administered OVs is limited due to rapid immune clearance and suboptimal biodistribution, while locally administered OVs encounter an additional barrier of poor bioavailability. Cell-based carriers that can shield viral particles and provide tumor-targeted OV delivery, represent one of the potential ways to address these challenges. The feasibility of this approach was demonstrated using a broad range of cell types, including mesenchymal stem cells (MSCs), neural stem cells (NSCs), different subsets of immune cells, and cancer cell lines. The resulting spectrum of carriers can be viewed as a multifaceted tool, taking into account the specific properties, advantages, and limitations of each cell carrier type discussed in this review. Careful consideration of these features will provide the basis for successful development of cell-based OV delivery platforms. Full article

Neural stem cells have shown great potential in the therapy of neurodegenerative diseases such as Parkinson’s disease (PD), because of their ability to differentiate into various types of neural cells and substitute for damaged neurons. Their clinical application is, however, impeded by limitations such as low survival rates following transplantation, low efficiency of differentiation, the potential for tumorigenesis, and the risk of immune rejection by the host. Adipose-derived stem cells (ADSCs) have become increasingly popular as an alternative tool in regenerative medicine due to their accessibility, multipotency, and low immunogenicity. The recent advance in inducing ADSCs into neural stem cell-like cells (iNSCs) opens up a new avenue for the treatment of PD by restoring dopaminergic neuron populations. Here, the biological characteristics, induction protocols, molecular mechanisms, and prospective applications of ADSCs in neural repair are summarized systematically. We also covered current technical challenges, such as differentiation protocol optimization and functional integration, and future perspectives, including biomaterial and gene editing applications to enhance ADSC-based therapies. With these challenges met, ADSCs hold excellent potential for advancing personalized and combination therapies for neurodegenerative diseases. Full article

Alzheimer’s disease (AD) is characterized by progressive cognitive decline strongly associated with impaired adult hippocampal neurogenesis (AHN). Mounting evidence suggests that this impairment results from both the intrinsic dysfunction of neural stem cells (NSCs)—such as transcriptional alterations in quiescent states—and extrinsic niche disruptions, including the dysregulation of the Reelin signaling pathway and heightened neuroinflammation. Notably, AHN deficits may precede classical amyloid-β and Tau pathology, supporting their potential as early biomarkers of disease progression. In this review, we synthesize recent advances in therapeutic strategies aimed at restoring AHN, encompassing pharmacological agents, natural products, and non-pharmacological interventions such as environmental enrichment and dietary modulation. Emerging approaches—including BDNF-targeted nanocarriers, NSC-derived extracellular vesicles, and multimodal lifestyle interventions—highlight the translational promise of enhancing neurogenesis in models of familial AD. We further propose the Neurogenesis Impairment Index (NII)—a novel composite metric that quantifies hippocampal neurogenic capacity relative to amyloid burden, while adjusting for demographic and cognitive variables. By integrating neurogenic potential, cognitive performance, and pathological load, NII provides a framework for stratifying disease severity and guiding personalized therapeutic approaches. Despite ongoing challenges—such as interspecies differences in neurogenesis rates and the limitations of stem cell-based therapies—this integrative perspective offers a promising avenue to bridge mechanistic insights with clinical innovation in the development of next-generation AD treatments. Full article

Spinal cord injury (SCI) is a debilitating neurological condition that leads to severe disabilities, significantly reducing patients’ quality of life and imposing substantial societal and economic burdens. SCI involves a complex pathogenesis, including primary irreversible damage and secondary injury driven by neuroinflammation, apoptosis, and ischemia. Current treatments often provide limited efficacy, underscoring the urgent need for innovative therapeutic strategies. This paper aims to explore the potential use of stem cell (SC) therapy and exosome-based treatments as transformative approaches for managing SCI and mitigating associated disabilities. SCs, such as mesenchymal stem cells (MSCs), neural stem cells (NSCs), and embryonic stem cells (ESCs), demonstrate regenerative capabilities, including self-renewal, differentiation into neurons and glial cells, and modulation of the injury microenvironment. These properties enable SCs to reduce inflammation, inhibit apoptosis, and promote neuronal regeneration in preclinical models. Exosome-based therapies, derived from SCs, offer a novel alternative by addressing challenges like immune rejection and tumorigenicity. Exosomes deliver biomolecules, such as miRNAs, fostering anti-inflammatory, anti-apoptotic, and pro-regenerative effects. They have shown efficacy in improving motor function, reducing glial scarring, and enhancing axonal regrowth in SCI models. The objective of this paper is to provide a comprehensive review of SC therapy and exosome-based approaches, emphasizing their potential to revolutionize SCI management while addressing ethical concerns, immune rejection, and the need for large-scale clinical trials. These therapies hold promise for improving recovery outcomes and alleviating the profound disabilities associated with SCI. Full article

Neural stem cells (NSCs) are crucial components of the nervous system, primarily located in the subventricular zone (SVZ) and subgranular zone (SGZ). The SVZ neural stem cell niche (NSCN) is a specialized microenvironment where growth factors and extracellular matrix (ECM) components collaborate to regulate NSC self-renewal and differentiation. Despite its importance, our understanding of the SVZ remains incomplete due to the inherent challenges of animal research, particularly given the tissue’s dynamic nature. To address these limitations, we developed a proof-of-concept, dynamic, and tissue-specific 3D organotypic SVZ model to reduce reliance on animal models. This static 3D organotypic model integrates a region-specific decellularized ECM derived from the SVZ, mimicking the native NSCN and supporting mouse-derived ependymal cells (ECs), radial glial cells (RGCs), astrocytes, and NSCs. To further improve physiological relevance, we incorporated a dynamic microfluidic culture system (SVZonChip), replicating cerebrospinal fluid (CSF) flow as observed in vivo. The resulting SVZonChip platform, combining region-specific ECM proteins with dynamic culture conditions, provides a sustainable and reproducible tool to minimize animal model use. It holds significant promise for studying SVZ-related diseases, such as congenital hydrocephalus, stroke, and post-stroke neurogenesis, while advancing translational research and enabling personalized medicine protocols. Full article

Glioblastoma is a fatal and aggressive cancer with no cure. It is becoming increasingly clear that glioblastoma initiation is a result of adult neural stem cell (NSC) transformation—most likely those within the subventricular zone (SVZ). Indeed, transcriptomic analysis indicates that glioblastomas are reminiscent of a neurodevelopmental hierarchy, in which neural stem and progenitor markers are widely expressed by tumour stem-like cells. However, NSC fates and the cues that drive them are poorly understood. Studying the crosstalk within NSC niches may better inform our understanding of glioblastoma initiation and development. Insulin-like growth factor binding protein 2 (IGFBP-2) has a well-established prognostic role in glioblastoma, and cell-based mechanistic studies show the independent activation of downstream oncogenic pathways. However, IGFBP-2 is more commonly recognised as a modulator of insulin-like growth factors (IGFs) for receptor tyrosine kinase signal propagation or attenuation. In the adult human brain, both IGFBP-2 and IGF-II expression are retained in the choroid plexus (ChP) and secreted into the cerebral spinal fluid (CSF). Moreover, secretion by closely associated cells and NSCs themselves position IGFBP-2 and IGF-II as interesting factors within the NSC niche. In this review, we will highlight the experimental findings that show IGFBP-2 and IGF-II influence NSC behaviour. Moreover, we will link this to glioblastoma biology and demonstrate the requirement for further analysis of these factors in glioma stem cells (GSCs). Full article