Development Of Central Nervous System Research Articles

Extent of foetal exposure to maternal elexacaftor/tezacaftor/ivacaftor during pregnancy.

Cystic fibrosis (CF) patients are living longer and healthier due to improved treatments, e.g. cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy elexacaftor/tezacaftor/ivacaftor (ETI), with treatment possibly occurring in pregnancy. The risk of ETI to foetuses remain unknown. Thus the effect of maternally administered ETI on foetal genetic and structural development was investigated. Pregnant Sprague Dawley rats were orally treated with ETI (6.7mg·kg-1·day-1 elexacaftor + 3.5mg·kg-1·day-1 tezacaftor + 25 mg·kg-1·day-1 ivacaftor) for 7days from E12 to E19. Tissue samples collected at E19 were analysed using histology and RNA sequencing. Histological changes and differentially expressed genes (DEG) were assessed. No overt structural abnormalities were found in foetal pancreas, liver, lung and small intestine after 7-day ETI exposure. Very few non-functionally associated DEG in foetal liver, lung and small intestine were identified using RNA-seq. 29 DEG were identified in thymus (27 up-regulated and two down-regulated) and most were functionally linked to each other. Gene ontology enrichment analysis revealed that multiple muscle-related terms were significantly enriched. Many more DEG were identified in cortex (44 up-regulated and four down-regulated) and a group of these were involved in central nervous system and brain development. Sub-chronic ETI treatment in late pregnancy does not appear to pose a significant risk to the genetic and structural development of many foetal tissues. However, significant gene changes in foetal thymic myoid cells and cortical neuronal development requires future follow-up studies to assess the risk to these organs.

Spatiotemporal dynamics of the CD11c+ microglial population in the mouse brain and spinal cord from developmental to adult stages.

CD11c-positive (CD11c+) microglia have attracted considerable attention because of their potential implications in central nervous system (CNS) development, homeostasis, and disease. However, the spatiotemporal dynamics of the proportion of CD11c+ microglia in individual CNS regions are poorly understood. Here, we investigated the proportion of CD11c+ microglia in six CNS regions (forebrain, olfactory bulb, diencephalon/midbrain, cerebellum, pons/medulla, and spinal cord) from the developmental to adult stages by flow cytometry and immunohistochemical analyses using a CD11c reporter transgenic mouse line, Itgax-Venus. We found that the proportion of CD11c+ microglia in total microglia varied between CNS regions during postnatal development. Specifically, the proportion was high in the olfactory bulb and cerebellum at postnatal day P(4) and P7, respectively, and approximately half of the total microglia were CD11c+. The proportion declined sharply in all regions to P14, and the low percentage persisted over P56. In the spinal cord, the proportion of CD11c+ microglia was also high at P4 and declined to P14, but increased again at P21 and thereafter. Interestingly, the distribution pattern of CD11c+ microglia in the spinal cord markedly changed from gray matter at P4 to white matter at P21. Collectively, our findings reveal the differences in the spatiotemporal dynamics of the proportion of CD11c+ microglia among CNS regions from early development to adult stages in normal mice. These findings improve our understanding of the nature of microglial heterogeneity and its dynamics in the CNS.

Exploring Ca2+ Dynamics in Myelinating Oligodendrocytes through rAAV-Mediated jGCaMP8s Expression in Developing Spinal Cord Organ Cultures.

Oligodendrocytes, the myelin-producing glial cells of the central nervous system (CNS), crucially contribute to myelination and circuit function. An increasing amount of evidence suggests that intracellular calcium (Ca2+) dynamics in oligodendrocytes mediates activity-dependent and activity-independent myelination. Unraveling how myelinating oligodendrocytes orchestrate and integrate Ca2+ signals, particularly in relation to axonal firing, is crucial for gaining insights into their role in the CNS development and function, both in health and disease. In this framework, we used the recombinant adeno-associated virus/Olig001 capsid variant to express the genetically encoded Ca2+ indicator jGCaMP8s, under the control of the myelin basic protein promoter. In our study, this tool exhibits excellent tropism and selectivity for myelinating and mature oligodendrocytes, and it allows monitoring Ca2+ activity in myelin-forming cells, both in isolated primary cultures and organotypic spinal cord explants. By live imaging of myelin Ca2+ events in oligodendrocytes within organ cultures, we observed a rapid decline in the amplitude and duration of Ca2+ events across different in vitro developmental stages. Active myelin sheath remodeling and growth are modulated at the level of myelin-axon interface through Ca2+ signaling, and, during early myelination in organ cultures, this phase is finely tuned by the firing of axon action potentials. In the later stages of myelination, Ca2+ events in mature oligodendrocytes no longer display such a modulation, underscoring the involvement of complex Ca2+ signaling in CNS myelination.

Selective sweep analysis of the adaptability of the Yarkand hare (Lepus yarkandensis) to hot arid environments using SLAF-seq.

The Yarkand hare (Lepus yarkandensis) inhabits arid desert areas and is endemic to China. It has evolved various adaptations to survive in hot arid environments, including stress responses, the ability to maintain water homeostasis and heat tolerance. Here, we performed a selective sweep analysis to identify the candidate genes for adaptation to hot arid environments in the Yarkand hare. A total of 397 237 single-nucleotide polymorphisms were obtained from 80 Yarkand hares, which inhabit hot arid environments, and 36 Tolai hares (Lepus tolai), which inhabit environments with a mild climate, via specific-locus amplified fragment sequencing. We identified several candidate genes that were associated with the heat stress response (HSPE1), oxidative stress response (SLC23A and GLRX2), immune response (IL1R1 and IRG1), central nervous system development (FGF13, THOC2, FMR1 and MECP2) and regulation of water homeostasis (CDK1) according to fixation index values and θπ ratios in the selective sweep analysis, and six of these genes (GLRX2, IRG1, FGF13, FMR1, MECP2 and CDK1) are newly discovered genes. To the best of our knowledge, this is the first study to identify candidate genes for adaptation to hot arid environments in the Yarkand hare. The results of this study enhance our understanding of the adaptation of the Yarkand hare to hot arid environments and will aid future studies aiming to functionally verify these candidate genes.

Comparing the Developmental Toxicity Delay and Neurotoxicity of Benzothiazole and Its Derivatives (BTHs) in Juvenile Zebrafish.

In this study, a semi-static water exposure method was employed to investigate the early developmental and neurotoxic effects of four benzothiazole substances (BTHs), namely benzothiazole (BTH), 2-mercaptobenzothiazole (MBT), 2-hydroxybenzothiazole (BTON), and 2-aminobenzothiazole (2-ABTH), on zebrafish at an equimolar concentration of 10 μM. The findings revealed that all four BTHs exerted certain impacts on early development in zebrafish. MBT stimulated spontaneous movement in juvenile zebrafish, whereas BTON inhibited such movements. Moreover, all four BTHs hindered the hatching process of zebrafish larvae, with MBT exhibiting the strongest inhibition at 24 h post-fertilization (hpf). Notably, MBT acted as a melanin inhibitor by suppressing melanin production in juvenile zebrafish eyes and weakening phototaxis. Additionally, both BTH and BTON exhibited significantly lower speeds than the control group and other test groups under conditions without bright field stimulation; however, their speeds increased to average levels after percussion stimulation, indicating no significant alteration in motor ability among experimental zebrafish groups. Short-term exposure to these four types of BTHs induced oxidative damage in zebrafish larvae; specifically, BTH-, MBT-, and BTON-exposed groups displayed abnormal expression patterns of genes related to oxidative damage. Exposure to both BTH and MBT led to reduced fluorescence intensity in transgenic zebrafish labeled with central nervous system markers, suggesting inhibition of central nervous system development. Furthermore, real-time quantitative PCR results demonstrated abnormal gene expression associated with neural development. However, no significant changes were observed in 2-ABTH gene expression at this concentration. Overall findings indicate that short-term exposure to BTHs stimulates neurodevelopmental gene expression accompanied by oxidative damage.

A TH17-intrinsic IL-1β-STAT5 axis drives steroid resistance in autoimmune neuroinflammation.

Steroid resistance poses a major challenge for the management of autoimmune neuroinflammation. T helper 17 (TH17) cells are widely implicated in the pathology of steroid resistance; however, the underlying mechanisms are unknown. In this study, we identified that interleukin-1 receptor (IL-1R) blockade rendered experimental autoimmune encephalomyelitis (EAE) mice sensitive to dexamethasone (Dex) treatment. Interleukin-1β (IL-1β) induced a signal transducer and activator of transcription 5 (STAT5)-mediated steroid-resistant transcriptional program in TH17 cells, which promoted inflammatory cytokine production and suppressed Dex-induced anti-inflammatory genes. TH17-specific deletion of STAT5 ablated the IL-1β-induced steroid-resistant transcriptional program and rendered EAE mice sensitive to Dex treatment. IL-1β synergized with Dex to promote the STAT5-dependent expression of CD69 and the development of central nervous system (CNS)-resident CD69+ TH17 cells. Combined IL-1R blockade and Dex treatment ablated CNS-resident TH17 cells, reduced EAE severity, and prevented relapse. CD69+ tissue-resident TH17 cells were also detected in brain lesions of patients with multiple sclerosis. These findings (i) demonstrate that IL-1β-STAT5 signaling in TH17 cells mediates steroid resistance and (ii) identify a therapeutic strategy for reversing steroid resistance in TH17-mediated CNS autoimmunity.

Drosophila TET acts with PRC1 to activate gene expression independently of its catalytic activity.

Enzymes of the ten-eleven translocation (TET) family play a key role in the regulation of gene expression by oxidizing 5-methylcytosine (5mC), a prominent epigenetic mark in many species. Yet, TET proteins also have less characterized noncanonical modes of action, notably in Drosophila, whose genome is devoid of 5mC. Here, we show that Drosophila TET activates the expression of genes required for larval central nervous system (CNS) development mainly in a catalytic-independent manner. Genome-wide profiling shows that TET is recruited to enhancer and promoter regions bound by Polycomb group complex (PcG) proteins. We found that TET interacts and colocalizes on chromatin preferentially with Polycomb repressor complex 1 (PRC1) rather than PRC2. Furthermore, PRC1 but not PRC2 is required for the activation of TET target genes. Last, our results suggest that TET and PRC1 binding to activated genes is interdependent. These data highlight the importance of TET noncatalytic function and the role of PRC1 for gene activation in the Drosophila larval CNS.

Falls, fracture and frailty risk in multiple sclerosis: a Mendelian Randomization study to identify shared genetics

IntroductionPatients with multiple sclerosis (MS) commonly present musculoskeletal disorders characterized by lower bone mineral density (BMD) and muscle weakness. However, the underlying etiology remains unclear. Our objective is to identify shared pleiotropic genetic effects and estimate the causal relationship between MS and musculoskeletal disorders.Materials and MethodsWe conducted linkage disequilibrium score regression (LDSR), colocalization, and Mendelian randomization (MR) analyses using summary statistics from recent large-scale genome-wide association studies (GWAS), encompassing MS, falls, fractures, and frailty. Additional MR analyses explored the causal relationship with musculoskeletal risk factors, such as BMD, lean mass, grip strength, and vitamin D.ResultsWe observed a moderate genetic correlation between MS and falls (RG = 0.10, P-value =0.01) but not between MS with fracture or frailty in the LDSR analyses. MR revealed MS had no causal association with fracture and frailty but a moderate association with falls (OR: 1.004, FDR q-value = 0.018). We further performed colocalization analyses using nine SNPs that exhibited significant associations with both MS and falls in MR. Two SNPs (rs7731626 on ANKRD55 and rs701006 on OS9 gene) showed higher posterior probability of colocalization (PP.H4 = 0.927), suggesting potential pleiotropic effects between MS and falls. The nine genes are associated with central nervous system development and inflammation signaling pathways.ConclusionWe found potential pleiotropic genetic effects between MS and falls. However, our analysis did not reveal a causal relationship between MS and increased risks of falls, fractures, or frailty. This suggests that the musculoskeletal disorders frequently reported in MS patients in clinical studies are more likely attributed to secondary factors associated with disease progression and treatment, rather than being directly caused by MS itself.

Glial Cell Development and Function in the Zebrafish Central Nervous System.

Over the past decades the zebrafish has emerged as an excellent model organism with which to study the biology of all glial cell types in nervous system development, plasticity, and regeneration. In this review, which builds on the earlier work by Lyons and Talbot in 2015, we will summarize how the relative ease to manipulate the zebrafish genome and its suitability for intravital imaging have helped understand principles of glial cell biology with a focus on oligodendrocytes, microglia, and astrocytes. We will highlight recent findings on the diverse properties and functions of these glial cell types in the central nervous system and discuss open questions and future directions of the field.

Generation and characterization of cerebellar granule neurons specific knockout mice of Golli-MBP

Golli–myelin basic proteins, encoded by the myelin basic protein gene, are widely expressed in neurons and oligodendrocytes in the central nervous system. Further, prior research has shown that Golli–myelin basic protein is necessary for myelination and neuronal maturation during central nervous system development. In this study, we established Golli–myelin basic protein-floxed mice to elucidate the cell-type-specific effects of Golli–myelin basic protein knockout through the generation of conditional knockout mice (Golli–myelin basic proteinsfl/fl; E3CreN), in which Golli–myelin basic proteins were specifically deleted in cerebellar granule neurons, where Golli–myelin basic proteins are expressed abundantly in wild-type mice. To investigate the role of Golli–myelin basic proteins in cerebellar granule neurons, we further performed histopathological analyses of these mice, with results indicating no morphological changes or degeneration of the major cellular components of the cerebellum. Furthermore, behavioral analysis showed that Golli–myelin basic proteinsfl/fl; E3CreN mice were healthy and did not display any abnormal behavior. These results suggest that the loss of Golli–myelin basic proteins in cerebellar granule neurons does not lead to cerebellar perturbations or behavioral abnormalities. This mouse model could therefore be employed to analyze the effect of Golli–myelin basic protein deletion in specific cell types of the central nervous system, such as other neuronal cells and oligodendrocytes, or in lymphocytes of the immune system.

BTK inhibition limits microglia-perpetuated CNS inflammation and promotes myelin repair

In multiple sclerosis (MS), persisting disability can occur independent of relapse activity or development of new central nervous system (CNS) inflammatory lesions, termed chronic progression. This process occurs early and it is mostly driven by cells within the CNS. One promising strategy to control progression of MS is the inhibition of the enzyme Bruton's tyrosine kinase (BTK), which is centrally involved in the activation of both B cells and myeloid cells, such as macrophages and microglia. The benefit of BTK inhibition by evobrutinib was shown as we observed reduced pro-inflammatory activation of microglia when treating chronic experimental autoimmune encephalomyelitis (EAE) or following the adoptive transfer of activated T cells. Additionally, in a model of toxic demyelination, evobrutinib-mediated BTK inhibition promoted the clearance of myelin debris by microglia, leading to an accelerated remyelination. These findings highlight that BTK inhibition has the potential to counteract underlying chronic progression of MS.

Nutritional Quality Implications: Exploring the Impact of a Fatty Acid-Rich Diet on Central Nervous System Development.

Given the comprehensive examination of the role of fatty acid-rich diets in central nervous system development in children, this study bridges significant gaps in the understanding of dietary effects on neurodevelopment. It delves into the essential functions of fatty acids in neurodevelopment, including their contributions to neuronal membrane formation, neuroinflammatory modulation, neurogenesis, and synaptic plasticity. Despite the acknowledged importance of these nutrients, this review reveals a lack of comprehensive synthesis in current research, particularly regarding the broader spectrum of fatty acids and their optimal levels throughout childhood. By consolidating the existing knowledge and highlighting critical research gaps, such as the effects of fatty acid metabolism on neurodevelopmental disorders and the need for age-specific dietary guidelines, this study sets a foundation for future studies. This underscores the potential of nutritional strategies to significantly influence neurodevelopmental trajectories, advocating an enriched academic and clinical understanding that can inform dietary recommendations and interventions aimed at optimizing neurological health from infancy.

Calcium and Neural Stem Cell Proliferation.

Intracellular calcium plays a pivotal role in central nervous system (CNS) development by regulating various processes such as cell proliferation, migration, differentiation, and maturation. However, understanding the involvement of calcium (Ca2+) in these processes during CNS development is challenging due to the dynamic nature of this cation and the evolving cell populations during development. While Ca2+ transient patterns have been observed in specific cell processes and molecules responsible for Ca2+ homeostasis have been identified in excitable and non-excitable cells, further research into Ca2+ dynamics and the underlying mechanisms in neural stem cells (NSCs) is required. This review focuses on molecules involved in Ca2+ entrance expressed in NSCs in vivo and in vitro, which are crucial for Ca2+ dynamics and signaling. It also discusses how these molecules might play a key role in balancing cell proliferation for self-renewal or promoting differentiation. These processes are finely regulated in a time-dependent manner throughout brain development, influenced by extrinsic and intrinsic factors that directly or indirectly modulate Ca2+ dynamics. Furthermore, this review addresses the potential implications of understanding Ca2+ dynamics in NSCs for treating neurological disorders. Despite significant progress in this field, unraveling the elements contributing to Ca2+ intracellular dynamics in cell proliferation remains a challenging puzzle that requires further investigation.

Dissecting the networks underlying diverse brain disorders after prenatal glucocorticoid overexposure.

New human life begins in the uterus in a period of both extreme plasticity and sensitivity to environmental disturbances. The fetal stage is also a vital period for central nervous system development, with experiences at this point profoundly and permanently shaping brain structure and function. As such, some brain disorders may originate in utero. Glucocorticoids, a class of essential stress hormones, play indispensable roles in fetal development, but overexposure may have lasting impacts on the brain. In this review, we summarize data from recent clinical and non-clinical studies regarding alterations in fetal brains due to prenatal glucocorticoid overexposure that are associated with nervous system disorders. We discuss relevant changes to brain structure and cellular functions and explore the underlying molecular mechanisms. In addition, we summarize factors that may cause differential outcomes between varying brain regions, and outline clinically feasible intervention strategies that are expected to minimize negative consequences arising from fetal glucocorticoid overexposure. Finally, we highlight the need for experimental evidence aided by new technologies to clearly determine the effects of excessive prenatal glucocorticoid exposure. This review consolidates diverse findings to help researchers better understand the relationship between the prenatal glucocorticoid overexposure and the effects it has on various fetal brain regions, promoting further development of critical intervention strategies.

A Custom Panel for Profiling Microglia Gene Expression.

Despite being immune cells of the central nervous system (CNS), microglia contribute to CNS development, maturation, and homeostasis, and microglia dysfunction has been implicated in several neurological disorders. Recent advancements in single-cell studies have uncovered unique microglia-specific gene expression. However, there is a need for a simple yet elegant multiplexed approach to quantifying microglia gene expression. To address this, we have designed a NanoString nCounter technology-based murine microglia-specific custom codeset comprising 178 genes. We analyzed RNA extracted from ex vivo adult mouse microglia, primary mouse microglia, the BV2 microglia cell line, and mouse bone marrow monocytes using our custom panel. Our findings reveal a pattern where homeostatic genes exhibit heightened expression in adult microglia, followed by primary cells, and are absent in BV2 cells, while reactive markers are elevated in primary microglia and BV2 cells. Analysis of publicly available data sets for the genes present in the panel revealed that the panel could reliably reflect the changes in microglia gene expression in response to various factors. These findings highlight that the microglia panel used offers a swift and cost-effective means to assess microglial cells and can be used to study them in varying contexts, ranging from normal homeostasis to disease models.

Iron deficiency in astrocytes alters cellular status and impacts on oligodendrocyte differentiation.

Iron deficiency (ID) has been shown to affect central nervous system (CNS) development and induce hypomyelination. Previous work from our laboratory in a gestational ID model showed that both oligodendrocyte (OLG) and astrocyte (AST) maturation was impaired. To explore the contribution of AST iron to the myelination process, we generated an invitro ID model by silencing divalent metal transporter 1 (DMT1) in AST (siDMT1 AST) or treating AST with Fe3+ chelator deferoxamine (DFX; DFX AST). siDMT1 AST showed no changes in proliferation but remained immature. Co-cultures of oligodendrocyte precursors cells (OPC) with siDMT1 AST and OPC cultures incubated with siDMT1 AST-conditioned media (ACM) rendered a reduction in OPC maturation. These findings correlated with a decrease in the expression of AST-secreted factors IGF-1, NRG-1, and LIF, known to promote OPC differentiation. siDMT1 AST also displayed increased mitochondrial number and reduced mitochondrial size as compared to control cells. DFX AST also remained immature and DFX AST-conditioned media also hampered OPC maturation in culture, in keeping with a decrease in the expression of AST-secreted growth factors IGF-1, NRG-1, LIF, and CNTF. DFX AST mitochondrial morphology and number showed results similar to those observed in siDMT1 AST. In sum, our results show that ID, induced through two different methods, impacts AST maturation and mitochondrial functioning, which in turn hampers OPC differentiation.

Detection of abnormal behaviors in prenatal Poly(I:C) exposed mice in a group-rearing environment.

During pregnancy, the maternal environment is critical for normal ontogeny and central nervous system development. Occasionally, prenatal exposure to environmental factors affects tissue architecture and functional development of the brain, which causes developmental disorders, including disorders of the autism spectrum. One of these environmental factors is the exposure to infectious diseases during pregnancy. In this study, we generated mice with infectious disease-induced inflammation by prenatal exposure to 200 μg/kg polyinosinic-polycytidylic acid sodium salt [Poly(I:C)] at embryonic day 12.5 and analyzed their phenotypes on 30-weeks-old. We attempted to detect abnormalities in spontaneous activity and social interaction, which may be indicators of developmental disorder-like behavioral abnormalities, in free-ranging behaviors in multiple rearing environments using multiple animal positioning systems and UMATracker in mice with fetal inflammation. Increased spontaneous activity and abnormal social interactions were observed in mice in the Poly(I:C)-treated group compared with those in the control group. Prenatal exposure to Poly(I:C) increased motor activity and decreased social interaction, and social behavior in prenatally treated mice in a multiple-individual rearing environment. Poly(I:C) exposure during the fetal period resulted in developmental disorder-like behavioral abnormalities, such as increased activity and abnormal social interactions, even after maturation in a multiple-individual rearing environment. This experimental method may provide a new way to analyze the behavior of mouse models of developmental disorders in a multiple-individual rearing environment, in which free-ranging behavior is possible.

Reduced mTORC1-signaling in progenitor cells leads to retinal lamination deficits.

Neuronal lamination is a hallmark of the mammalian central nervous system (CNS) and underlies connectivity and function. Initial formation of this tissue architecture involves the integration of various signaling pathways that regulate the differentiation and migration of neural progenitor cells. Here, we demonstrate that mTORC1 mediates critical roles during neuronal lamination using the mouse retina as a model system. Down-regulation of mTORC1-signaling in retinal progenitor cells by conditional deletion of Rptor led to decreases in proliferation and increased apoptosis during embryogenesis. These developmental deficits preceded aberrant lamination in adult animals which was best exemplified by the fusion of the outer and inner nuclear layer and the absence of an outer plexiform layer. Moreover, ganglion cell axons originating from each Rptor-ablated retina appeared to segregate to an equal degree at the optic chiasm with both contralateral and ipsilateral projections displaying overlapping termination topographies within several retinorecipient nuclei. In combination, these visual pathway defects led to visually mediated behavioral deficits. This study establishes a critical role for mTORC1-signaling during retinal lamination and demonstrates that this pathway regulates diverse developmental mechanisms involved in driving the stratified arrangement of neurons during CNS development.

A Disintegrin And Metalloprotease 10 expression within the murine central nervous system

A Disintegrin And Metalloprotease 10 (ADAM10), is able to control several important physiopathological processes through the shedding of a large number of protein substrates. Although ADAM10 plays a crucial role in the central nervous system (CNS) development and function, its protein distribution in the CNS has not been fully addressed. Here, we described the regional and cellular ADAM10 protein expression in C57BL/6 mice examined by immunofluorescence 1) throughout the adult mouse brain, cerebellum and spinal cord in vivo and 2) in different cell types as neurons, astrocytes, oligodendrocytes and microglia in vitro. We observed ADAM10 expression through the whole CNS, with a strong expression in the hippocampus, in the hypothalamus and in the cerebral and piriform cortex in the brain, in the Purkinje and in granular cell layers in the cerebellum and in the spinal cord to a lower extent. In vivo, ADAM10 protein expression was mainly found in neurons and in some oligodendroglial cell populations. However, in primary cultures we observed ADAM10 expression in neurons, oligodendrocytes, astrocytes and microglia. Interestingly, ADAM10 was not only found in the membrane but also in cytoplasmic vesicles and in the nucleus of primary cultured cells. Overall, this work highlights a wide distribution of ADAM10 throughout the CNS. The nuclear localization of ADAM10, probably due to its intracellular domain, emphasizes its role in cell signalling in physiological and pathological conditions. Further investigations are required to better elucidate the role of ADAM10 in glial cells.

Single-cell Profiling of Reprogrammed Human Neural Stem Cells Unveils High Similarity to Neural Progenitors in the Developing Central Nervous System.

Similar to induced pluripotent cells (iPSCs), induced neural stem cells (iNSCs) can be directly converted from human somatic cells such as dermal fibroblasts and peripheral blood monocytes. While previous studies have demonstrated the resemblance of iNSCs to neural stem cells derived from primary sources and embryonic stem cells, respectively, a comprehensive analysis of the correlation between iNSCs and their physiological counterparts remained to be investigated. Nowadays, single-cell sequencing technologies provide unique opportunities for in-depth cellular benchmarking of complex cell populations. Our study involves the comprehensive profiling of converted human iNSCs at a single-cell transcriptomic level, alongside conventional methods, like flow cytometry and immunofluorescence stainings. Our results show that the iNSC conversion yields a homogeneous cell population expressing bona fide neural stem cell markers. Extracting transcriptomic signatures from published single cell transcriptomic atlas data and comparison to the iNSC transcriptome reveals resemblance to embryonic neuroepithelial cells of early neurodevelopmental stages observed in vivo at 5 weeks of development. Our data underscore the physiological relevance of directly converted iNSCs, making them a valuable in vitro system for modeling human central nervous system development and establishing translational applications in cell therapy and compound screening.