Comparative insight into the regenerative mechanisms of the adult brain in zebrafish and mouse: highlighting the importance of the immune system and inflammation in successful regeneration.

Regeneration, the complex process of restoring damaged or absent cells, tissues, and organs, varies considerably between species. The zebrafish is a remarkable model organism for its impressive regenerative abilities, particularly in organs such as the heart, fin, retina, spinal cord, and brain. Unlike mammals, zebrafish can regenerate with limited or absent scarring, a phenomenon closely linked to the activation of stem cells and immune cells. This review examines the unique roles played by the immune response and inflammation in zebrafish and mouse during regeneration, highlighting the cellular and molecular mechanisms behind their divergent regenerative capacities. By focusing on zebrafish telencephalic regeneration and comparing it to that of the rodents, this review highlights the importance of a well-controlled, acute, and non-persistent immune response in zebrafish, which promotes an environment conducive to regeneration. The knowledge gained from understanding the mechanisms of zebrafish regeneration holds great promises for the treatment of human neurodegenerative diseases and brain damage (stroke and traumatic brain injuries), as well as for the advancement of regenerative medicine approaches.

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

BACKGROUND: Inadequate 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. METHODS: The 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. RESULTS: Metformin 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). CONCLUSION: Metformin, 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.

SIRT1-driven mechanism: sevoflurane's interference with mESC neural differentiation via PRRX1/DRD2 cascade.

Investigating the sevoflurane-induced perturbation in the differentiation of mouse embryonic stem cells (mESCs) into neural stem cells (mNSCs), our study delineates a novel SIRT1/PRRX1/DRD2/PKM2/NRF2 axis as a key player in this intricate process. Sevoflurane treatment hindered mESC differentiation, evidenced by altered expression patterns of pluripotency and neural lineage markers. Mechanistically, sevoflurane downregulated Sirt1, setting in motion a signaling cascade. Sevoflurane may inhibit PKM2 dimerization and NRF2 signaling pathway activation by inhibiting the expression of SIRT1 and its downstream genes Prrx1 and DRD2, ultimately inhibiting mESCs differentiation into mNSCs. These findings contribute to our understanding of the molecular basis of sevoflurane-induced neural toxicity, presenting a potential avenue for therapeutic intervention in sevoflurane-induced perturbation in the differentiation of mESCs into mNSCs by modulating the SIRT1/PRRX1/DRD2/PKM2/NRF2 axis.

The crosstalk between oxidative stress and DNA damage induces neural stem cell senescence by HO-1/PARP1 non-canonical pathway.

Neural stem cells play a crucial role in maintaining brain homeostasis. Neural stem cells senescence can lead to the decline of nerve repair and regeneration, causing brain aging and neurodegenerative diseases. However, the mechanism underlying neural stem cells senescence remains poorly understood. In this study, we report a novel HO-1/PARP1 non-canonical pathway highlighting how oxidative stress triggers the DNA damage response, ultimately leading to premature cellular senescence in neural stem cells. HO-1 acts as a sensor for oxidative stress, while PARP1 functions as a sensor for DNA damage. The simultaneous expression and molecular interaction of these two sensors can initiate a crosstalk of oxidative stress and DNA damage response processes, leading to the vicious cycle. The persistent activation of this pathway contributes to the senescence of neural stem cells, which in turn plays a crucial role in the progression of neurodegenerative diseases. Consequently, targeting this novel signaling pathway holds promise for the development of innovative therapeutic strategies and targets aimed at mitigating neural stem cells senescence-related disorders.

The roles of neural stem cells in myelin regeneration and repair therapy after spinal cord injury.

Spinal cord injury (SCI) is a complex tissue injury that results in a wide range of physical deficits, including permanent or progressive disabilities of sensory, motor and autonomic functions. To date, limitations in current clinical treatment options can leave SCI patients with lifelong disabilities. There is an urgent need to develop new therapies for reconstructing the damaged spinal cord neuron-glia network and restoring connectivity with the supraspinal pathways. Neural stem cells (NSCs) possess the ability to self-renew and differentiate into neurons and neuroglia, including oligodendrocytes, which are cells responsible for the formation and maintenance of the myelin sheath and the regeneration of demyelinated axons. For these properties, NSCs are considered to be a promising cell source for rebuilding damaged neural circuits and promoting myelin regeneration. Over the past decade, transplantation of NSCs has been extensively tested in a variety of preclinical models of SCI. This review aims to highlight the pathophysiology of SCI and promote the understanding of the role of NSCs in SCI repair therapy and the current advances in pathological mechanism, pre-clinical studies, as well as clinical trials of SCI via NSC transplantation therapeutic strategy. Understanding and mastering these frontier updates will pave the way for establishing novel therapeutic strategies to improve the quality of recovery from SCI.

Roles of cerebrospinal fluid-contacting neurons as potential neural stem cells in the repair and regeneration of spinal cord injuries.

Cerebrospinal fluid-contacting neurons (CSF-cNs) represent a distinct group of interneurons characterized by their prominent apical globular protrusions penetrating the spinal cord's central canal and their basal axons extending towards adjacent cells. Identified nearly a century back, the specific roles and attributes of CSF-cNs have just started to emerge due to the historical lack of definitive markers. Recent findings have confirmed that CSF-cNs expressing PKD2L1 possess attributes of neural stem cells, suggesting a critical function in the regeneration processes following spinal cord injuries. This review aims to elucidate the molecular markers of CSF-cNs as potential neural stem cells during spinal cord development and assess their roles post-spinal cord injury, with an emphasis on their potential therapeutic implications for spinal cord repair.

Amniotic Membrane-Derived Multichannel Hydrogels for Neural Tissue Repair.

In the pursuit of advancing neural tissue regeneration, biomaterial scaffolds have emerged as promising candidates, offering potential solutions for nerve disruptions. Among these scaffolds, multichannel hydrogels, characterized by meticulously designed micrometer-scale channels, stand out as instrumental tools for guiding axonal growth and facilitating cellular interactions. This study explores the innovative application of human amniotic membranes modified with methacryloyl domains (AMMA) in neural stem cell (NSC) culture. AMMA hydrogels, possessing a tailored softness resembling the physiological environment, are prepared in the format of multichannel scaffolds to simulate native-like microarchitecture of nerve tracts. Preliminary experiments on AMMA hydrogel films showcase their potential for neural applications, demonstrating robust adhesion, proliferation, and differentiation of NSCs without the need for additional coatings. Transitioning into the 3D realm, the multichannel architecture fosters intricate neuronal networks guiding neurite extension longitudinally. Furthermore, the presence of synaptic vesicles within the cellular arrays suggests the establishment of functional synaptic connections, underscoring the physiological relevance of the developed neuronal networks. This work contributes to the ongoing efforts to find ethical, clinically translatable, and functionally relevant approaches for regenerative neuroscience.

Atoh1 overexpression promotes Guinea pig bone marrow mesenchymal stem cells to differentiate into neural stem cell.

Sensorineural hearing loss (SNHL) is a prevalent condition in otolaryngology. A key obstacle is finding effective strategies for regenerating damaged cochlear hair cells in adult animals. A practical and reliable approach has been developed to create a superior cell source for stem cell transplantation in the inner ear to treat SNHL. Atoh1 is involved in the differentiation of neurons, intestinal secretory cells, and mechanoreceptors including auditory hair cells, and thus plays an important role in neurogenesis. Lentivirus-mediated transfection of bone marrow mesenchymal stem cells (BMSCs) was utilized to achieve stable expression of the essential transcription factor Atoh1, which is crucial for developing auditory hair cells without compromising cell survival. By manipulating the induction conditions through altering the cell growth environment using anti-adherent culture, the synergistic impact of basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) was effectively applied to significantly improve the differentiation efficiency of bone marrow-derived mesenchymal stem cells (BMSC) into neural stem cells (NSCs) following Atoh1 transfection, thereby reducing the induction time. The study indicated that the newly proposed transdifferentiation method effectively transformed BMSCs into NSCs in a controlled environment, presenting a potential approach for stem cell transplantation to promote hair cell regeneration.

The Role of Smad3 in the Realization of the Growth Potential of Different Types of Neural Progenitor Cells and the Secretory Function of Neuroglia.

The features of the participation of Smad3 in the functioning of neural stem cells (NSC), neuronal committed precursors (NCP), and neuroglial elements were studied in vitro. It was found that this intracellular signaling molecule enhances the clonogenic and proliferative activities of NCP and inhibits specialization of neuronal precursors. At the same time, Smad3 does not participate in the realization of the growth potential of NSC. With regard to the secretory function (production of neurotrophic growth factors) of neuroglial cells, the stimulating role of Smad3-mediated signaling was shown. These results indicate the promise of studying the possibility of using Smad3 as a fundamentally new target for neuroregenerative agents.

Digirseophene A promotes recovery in injured developing cerebellum via AMPK/AKT/GSK3ß 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 GSK3ß 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/GSK3ß pathway.

Emergence of the ZNF675 Gene During Primate Evolution-Influenced Human Neurodevelopment Through Changing HES1 Autoregulation.

In this study, we investigated recurrent copy number variations (CNVs) in the 19p12 locus, which are associated with neurodevelopmental disorders. The two genes in this locus, ZNF675 and ZNF681, arose via gene duplication in primates, and their presence in several pathological CNVs in the human population suggests that either or both of these genes are required for normal human brain development. ZNF675 and ZNF681 are members of the Krüppel-associated box zinc finger (KZNF) protein family, a class of transcriptional repressors important for epigenetic silencing of specific genomic regions. About 170 primate-specific KZNFs are present in the human genome. Although KZNFs are primarily associated with repressing retrotransposon-derived DNA, evidence is emerging that they can be co-opted for other gene regulatory processes. We show that genetic deletion of ZNF675 causes developmental defects in cortical organoids, and our data suggest that part of the observed neurodevelopmental phenotype is mediated by a gene regulatory role of ZNF675 on the promoter of the neurodevelopmental gene Hes family BHLH transcription factor 1 (HES1). We also find evidence for the recently evolved regulation of genes involved in neurological disorders, microcephalin 1 and sestrin 3. We show that ZNF675 interferes with HES1 auto-inhibition, a process essential for the maintenance of neural progenitors. As a striking example of how some KZNFs have integrated into preexisting gene expression networks, these findings suggest the emergence of ZNF675 has caused a change in the balance of HES1 autoregulation. The association of ZNF675 CNV with human developmental disorders and ZNF675-mediated regulation of neurodevelopmental genes suggests that it evolved into an important factor for human brain development.

[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]. / å¤§é¼ è„‘å‡ºè¡€åŽå† æºæ€§ç¥žç»å¹²ç»†èƒžè¿ç§»å’Œå¾®çŽ¯å¢ƒä¸­å ç–«ç»†èƒžè¡¨åž‹å˜åŒ–è§„å¾‹çš„å ³ç³».

Objective: 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. Methods: 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. Results: 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. Conclusion: 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.

Chronic chemogenetic activation of hippocampal progenitors enhances adult neurogenesis and modulates anxiety-like behavior and fear extinction learning.

Adult hippocampal neurogenesis is a lifelong process that involves the integration of newborn neurons into the hippocampal network, and plays a role in cognitive function and the modulation of mood-related behavior. Here, we sought to address the impact of chemogenetic activation of adult hippocampal progenitors on distinct stages of progenitor development, including quiescent stem cell activation, progenitor turnover, differentiation and morphological maturation. We find that hM3Dq-DREADD-mediated activation of nestin-positive adult hippocampal progenitors recruits quiescent stem cells, enhances progenitor proliferation, increases doublecortin-positive newborn neuron number, accompanied by an acceleration of differentiation and morphological maturation, associated with increased dendritic complexity. Behavioral analysis indicated anxiolytic behavioral responses in transgenic mice subjected to chemogenetic activation of adult hippocampal progenitors at timepoints when newborn neurons are predicted to integrate into the mature hippocampal network. Furthermore, we noted an enhanced fear memory extinction on a contextual fear memory learning task in transgenic mice subjected to chemogenetic activation of adult hippocampal progenitors. Our findings indicate that hM3Dq-DREAD-mediated chemogenetic activation of adult hippocampal progenitors impacts distinct aspects of hippocampal neurogenesis, associated with the regulation of anxiety-like behavior and fear memory extinction.

Substrate stress relaxation regulates neural stem cell fate commitment.

Adult neural stem cells (NSCs) reside in the dentate gyrus of the hippocampus, and their capacity to generate neurons and glia plays a role in learning and memory. In addition, neurodegenerative diseases are known to be caused by a loss of neurons and glial cells, resulting in a need to better understand stem cell fate commitment processes. We previously showed that NSC fate commitment toward a neuronal or glial lineage is strongly influenced by extracellular matrix stiffness, a property of elastic materials. However, tissues in vivo are not purely elastic and have varying degrees of viscous character. Relatively little is known about how the viscoelastic properties of the substrate impact NSC fate commitment. Here, we introduce a polyacrylamide-based cell culture platform that incorporates mismatched DNA oligonucleotide-based cross-links as well as covalent cross-links. This platform allows for tunable viscous stress relaxation properties via variation in the number of mismatched base pairs. We find that NSCs exhibit increased astrocytic differentiation as the degree of stress relaxation is increased. Furthermore, culturing NSCs on increasingly stress-relaxing substrates impacts cytoskeletal dynamics by decreasing intracellular actin flow rates and stimulating cyclic activation of the mechanosensitive protein RhoA. Additionally, inhibition of motor-clutch model components such as myosin II and focal adhesion kinase partially or completely reverts cells to lineage distributions observed on elastic substrates. Collectively, our results introduce a unique system for controlling matrix stress relaxation properties and offer insight into how NSCs integrate viscoelastic cues to direct fate commitment.

Essential role of p21Waf1/Cip1 in the modulation of post-traumatic hippocampal Neural Stem Cells response.

BACKGROUND: Traumatic Brain Injury (TBI) represents one of the main causes of brain damage in young people and the elderly population with a very high rate of psycho-physical disability and death. TBI is characterized by extensive cell death, tissue damage and neuro-inflammation with a symptomatology that varies depending on the severity of the trauma from memory loss to a state of irreversible coma and death. Recently, preclinical studies on mouse models have demonstrated that the post-traumatic adult Neural Stem/Progenitor cells response could represent an excellent model to shed light on the neuro-reparative role of adult neurogenesis following damage. The cyclin-dependent kinase inhibitor p21Waf1/Cip1 plays a pivotal role in modulating the quiescence/activation balance of adult Neural Stem Cells (aNSCs) and in restraining the proliferation progression of progenitor cells. Based on these considerations, the aim of this work is to evaluate how the conditional ablation of p21Waf1/Cip1 in the aNSCS can alter the adult hippocampal neurogenesis in physiological and post-traumatic conditions. METHODS: We designed a novel conditional p21Waf1/Cip1 knock-out mouse model, in which the deletion of p21Waf1/Cip1 (referred as p21) is temporally controlled and occurs in Nestin-positive aNSCs, following administration of Tamoxifen. This mouse model (referred as p21 cKO mice) was subjected to Controlled Cortical Impact to analyze how the deletion of p21 could influence the post-traumatic neurogenic response within the hippocampal niche. RESULTS: The data demonstrates that the conditional deletion of p21 in the aNSCs induces a strong increase in activation of aNSCs as well as proliferation and differentiation of neural progenitors in the adult dentate gyrus of the hippocampus, resulting in an enhancement of neurogenesis and the hippocampal-dependent working memory. However, following traumatic brain injury, the increased neurogenic response of aNSCs in p21 cKO mice leads to a fast depletion of the aNSCs pool, followed by declined neurogenesis and impaired hippocampal functionality. CONCLUSIONS: These data demonstrate for the first time a fundamental role of p21 in modulating the post-traumatic hippocampal neurogenic response, by the regulation of the proliferative and differentiative steps of aNSCs/progenitor populations after brain damage.

Engineering 3D Scaffold-Free Nanoparticle-Laden Stem Cell Constructs for Piezoelectric Enhancement of Human Neural Tissue Formation and Function.

Electrical stimulation (ES) of cellular systems can be utilized for biotechnological applications and electroceuticals (bioelectric medicine). Neural cell stimulation especially has a long history in neuroscience research and is increasingly applied for clinical therapies. Application of ES via conventional electrodes requires external connectors and power sources, hindering scientific and therapeutic applications. Here engineering novel 3D scaffold-free human neural stem cell constructs with integrated piezoelectric nanoparticles for enhanced neural tissue induction and function is described. Tetragonal barium titanate (BaTi03) nanoparticles are employed as piezoelectric stimulators prepared as cytocompatible dispersions, incorporated into 3D self-organizing neural spheroids, and activated wirelessly by ultrasound. Ultrasound delivery (low frequency; 40 kHz) is optimized for cell survival, and nanoparticle activation enabled ES throughout the spheroids during differentiation, tissue formation, and maturation. The resultant human neural tissues represent the first example of direct tissue loading with piezoelectric particles for ensuing 3D ultrasound-mediated piezoelectric enhancement of human neuronal induction from stem cells, including augmented neuritogenesis and synaptogenesis. It is anticipated that the platform described will facilitate advanced tissue engineering and in vitro modeling of human neural (and potentially non-neural) tissues, with modeling including tissue development and pathology, and applicable to preclinical testing and prototyping of both electroceuticals and pharmaceuticals.

IPSC-NSCs-derived exosomal let-7b-5p improves motor function after spinal cord Injury by modulating microglial/macrophage pyroptosis.

BACKGROUND: Following spinal cord injury (SCI), the inflammatory storm initiated by microglia/macrophages poses a significant impediment to the recovery process. Exosomes play a crucial role in the transport of miRNAs, facilitating essential cellular communication through the transfer of genetic material. However, the miRNAs from iPSC-NSCs-Exos and their potential mechanisms leading to repair after SCI remain unclear. This study aims to explore the role of iPSC-NSCs-Exos in microglia/macrophage pyroptosis and reveal their potential mechanisms. METHODS: iPSC-NSCs-Exos were characterized and identified using transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blot. A mouse SCI model and a series of in vivo and in vitro experiments were conducted to investigate the therapeutic effects of iPSC-NSCs-Exos. Subsequently, miRNA microarray analysis and rescue experiments were performed to confirm the role of miRNAs in iPSC-NSCs-Exos in SCI. Mechanistic studies were carried out using Western blot, luciferase activity assays, and RNA-ChIP. RESULTS: Our findings revealed that iPSC-NSCs-derived exosomes inhibited microglia/macrophage pyroptosis at 7 days post-SCI, maintaining myelin integrity and promoting axonal growth, ultimately improving mice motor function. The miRNA microarray showed let-7b-5p to be highly enriched in iPSC-NSCs-Exos, and LRIG3 was identified as the target gene of let-7b-5p. Through a series of rescue experiments, we uncovered the connection between iPSC-NSCs and microglia/macrophages, revealing a novel target for treating SCI. CONCLUSION: In conclusion, we discovered that iPSC-NSCs-derived exosomes can package and deliver let-7b-5p, regulating the expression of LRIG3 to ameliorate microglia/macrophage pyroptosis and enhance motor function in mice after SCI. This highlights the potential of combined therapy with iPSC-NSCs-Exos and let-7b-5p in promoting functional recovery and limiting inflammation following SCI.

Evaluation of Gelatin-Based Poly(Ester Urethane Urea) Electrospun Fibers Using Human Mesenchymal and Neural Stem Cells.

Previously, a new biodegradable poly(ester urethane urea) was synthesized based on polycaprolactone-diol and fish gelatin (PU-Gel). In this work, the potential of this new material for neural tissue engineering is evaluated. Membranes with randomly oriented fibers and with aligned fibers are produced using electrospinning and characterized regarding their mechanical behavior under both dry and wet conditions. Wet samples exhibit a lower Young's modulus than dry ones and aligned membranes are stiffer and more brittle than those randomly oriented. Cyclic tensile tests are conducted and high values for recovery ratio and resilience are obtained. Both membranes exhibited a hydrophobic surface, measured by the water contact angle (WCA). Human mesenchymal stem cells from umbilical cord tissue (UC-MSCs) and human neural stem cells (NSCs) are seeded on both types of membranes, which support their adhesion and proliferation. Cells stained for the cytoskeleton and nucleus in membranes with aligned fibers display an elongated morphology following the alignment direction. As the culture time increased, higher cell viability is obtained on randomfibers for UC-MSCs while no differences are observed for NSCs. The membranes support neuronal differentiation of NSCs, as evidenced by markers for a neuronal filament protein (NF70) and for a microtubule-associated protein (MAP2).

Mitochondrial regulation of adult hippocampal neurogenesis: Insights into neurological function and neurodevelopmental disorders.

Mitochondria are essential regulators of cellular energy metabolism and play a crucial role in the maintenance and function of neuronal cells. Studies in the last decade have highlighted the importance of mitochondrial dynamics and bioenergetics in adult neurogenesis, a process that significantly influences cognitive function and brain plasticity. In this review, we examine the mechanisms by which mitochondria regulate adult neurogenesis, focusing on the impact of mitochondrial function on the behavior of neural stem/progenitor cells and the maturation and plasticity of newborn neurons in the adult mouse hippocampus. In addition, we explore the link between mitochondrial dysfunction, adult hippocampal neurogenesis and genes associated with cognitive deficits in neurodevelopmental disorders. In particular, we provide insights into how alterations in the transcriptional regulator NR2F1 affect mitochondrial dynamics and may contribute to the pathophysiology of the emerging neurodevelopmental disorder Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS). Understanding how genes involved in embryonic and adult neurogenesis affect mitochondrial function in neurological diseases might open new directions for therapeutic interventions aimed at boosting mitochondrial function during postnatal life.

Therapeutic Strategies for Ischemic Stroke: Modulating the Adult Neural Stem Cell Niche through the Wnt/ß-catenin Pathway.

Stroke is a prominent contributor to mortality and impairment on a global scale. Ischemic stroke accounts for approximately 80% of stroke cases and is caused by occlusion of cerebral blood vessels. Enhancing neurogenesis through the modulation of the neural stem cell niche in the adult brain is a promising therapeutic strategy for individuals afflicted with ischemic stroke. Neurogenesis results in the generation of newborn neurons that serve as replacements for deceased neural cells within the ischemic core, thereby playing a significant role in the process of neural restoration subsequent to cerebral ischemia. Research has shown that activation of the Wnt/ß-catenin pathway can augment neurogenesis following cerebral ischemia, suggesting that this pathway is a potentially beneficial therapeutic target for managing ischemic stroke. This review provides an extensive analysis of the current knowledge regarding the involvement of the Wnt/ß-catenin pathway in promoting neurogenesis, thereby offering a promising avenue for therapeutic intervention in the context of ischemic stroke or other neurological impairments.