Cellular and Molecular Neurobiology最新文献

The existence of lymphatic vessels or similar clearance systems in the central nervous system (CNS) that transport nutrients and remove cellular waste is a neuroscientific question of great significance. As the brain is the most metabolically active organ in the body, there is likely to be a potential correlation between its clearance system and the pathological state of the CNS. Until recently the successive discoveries of the glymphatic system and the meningeal lymphatics solved this puzzle. This article reviews the basic anatomy and physiology of the glymphatic system. Imaging techniques to visualize the function of the glymphatic system mainly including post-contrast imaging techniques, indirect lymphatic assessment by detecting increased perivascular space, and diffusion tensor image analysis along the perivascular space (DTI-ALPS) are discussed. The pathological link between glymphatic system dysfunction and neurological disorders is the key point, focusing on the enlarged perivascular space (EPVS) and the index of diffusivity along the perivascular space (ALPS index), which may represent the activity of the glymphatic system as possible clinical neuroimaging biomarkers of neurological disorders.

Graphical Abstract

The pathological link between glymphatic system dysfunction and neurological disorders is the key point, focusing on the enlarged perivascular space (EPVS) and the index for of diffusivity along the perivascular space (ALPS index), which may represent the activity of the glymphatic system as possible clinical neuroimaging biomarkers of neurological disorders

The adult peripheral nervous system has a significant ability for regeneration compared to the central nervous system. This is related to the unique neuroimmunomodulation after peripheral nerve injury (PNI). Unlike the repair of other tissues after injury, Schwann cells (SCs) respond immediately to the trauma and send out signals to precisely recruit macrophages to the injured site. Then, macrophages promote the degradation of the damaged myelin sheath by phagocytosis of local debris. At the same time, macrophages and SCs jointly secrete various cytokines to reconstruct a microenvironment suitable for nerve regeneration. This unique pathophysiological process associated with macrophages provides important targets for the repair and treatment of PNI, as well as an important reference for guiding the repair of other nerve injuries. To understand these processes more systematically, this paper describes the characteristics of macrophage activation and metabolism in PNI, discusses the underlying molecular mechanism of interaction between macrophages and SCs, and reviews the latest research progress of crosstalk regulation between macrophages and SCs. These concepts and therapeutic strategies are summarized to provide a reference for the more effective use of macrophages in the repair of PNI.

Intracranial vascular malformations manifest on a continuum ranging from predominantly arterial to predominantly venous in pathology. Cerebral cavernous malformations (CCMs) are capillary malformations that exist at the midpoint of this continuum. The axon guidance factor Ephrin B2 and its receptor EphB4 are critical regulators of vasculogenesis in the developing central nervous system. Ephrin B2/EphB4 dysregulation has been implicated in the pathogenesis of arterial-derived arteriovenous malformations and vein-based vein of Galen malformations. Increasing evidence supports the hypothesis that aberrant Ephrin B2/EphB4 signaling may contribute to developing vascular malformations, but their role in CCMs remains largely uncharacterized. Evidence of Ephrin dysregulation in CCMs would be important to establish a common link in the pathogenic spectrum of EphrinB2/Ephb4 dysregulation. By studying patient-derived primary CCM endothelial cells (CCMECs), we established that CCMECs are functionally distinct from healthy endothelial cell controls; CCMECs demonstrated altered patterns of migration, motility, and impaired tube formation. In addition to the altered phenotype, the CCMECs also displayed an increased ratio of EphrinB2/EphB4 compared to the healthy endothelial control cells. Furthermore, whole exome sequencing identified mutations in both EphrinB2 and EphB4 in the CCMECs. These findings identify functional alterations in the EphrinB2/EphB4 ratio as a feature linking pathophysiology across the spectrum of arterial, capillary, and venous structural malformations in the central nervous system while revealing a putative therapeutic target.

Gliomas, including anaplastic gliomas (AG; grade 3) and glioblastomas (GBM; grade 4), are malignant brain tumors associated with poor prognosis and low survival rates. Current classification systems based on histopathology have limitations due to intratumoral heterogeneity. The treatment and prognosis are distinctly different between grade 3 and grade 4 gliomas patients. Therefore, there is a need for molecular markers to differentiate these tumors accurately. In this study, we aimed to identify a gene expression signature using an artificial neural network (ANN) in application to microarray and serial analysis of gene expression (SAGE) data for grade 3 (AG) and grade 4 (GBM) gliomas discrimination. We acquired gene expression data from publicly available datasets on glial tumors of grades 3 and 4-a total of 93 grade 3 gliomas and 224 grade 4 gliomas. To select genes for classification, we implemented an artificial neural network-based method using a combination of self-organized maps (SOM) and perceptron. In general, we implemented a multi-stage procedure that involved multiple runs of a genetic algorithm to identify genes that provided optimal clusterization on the SOM. We performed this procedure multiple times, resulting in different sets of genes each time. Eventually, we selected several genes that appeared most frequently in the reduced sets and performed classification using them. Our analysis identified a set of seven genes (BCAS4, GLUD2, KCNJ10, KCND2, AKR7A2, FOLR1, and KIAA0319). The classification accuracy using this gene set was 87.5%. These findings suggest the potential of this gene set as a molecular marker for distinguishing grade 3 (AG) from grade 4 (GBM) gliomas.

Rhythmic regulations are virtually described in all physiological processes, including central nervous system development and immunologic responses. Zika virus (ZIKV), a neurotropic arbovirus, has been recently linked to a series of birth defects and neurodevelopmental disorders. Given the well-characterized role of the intrinsic cellular circadian clock within neurogenesis, cellular metabolism, migration, and differentiation among other processes, this study aimed to characterize the influence of ZIKV infection in the circadian clock expression in human neuronal cells. For this, in vitro models of human-induced neuroprogenitor cells (hiNPCs) and neuroblastoma cell line SH-SY5Y, cultured as monolayer and neurospheres, were infected by ZIKV, followed by RNA-Seq and RT-qPCR investigation, respectively. Targeted circadian clock components presented mRNA oscillations only after exogenous synchronizing stimuli (Forskolin) in SH-SY5Y monolayer culture. Interestingly, when these cells were grown as 3D-arranged neurospheres, an intrinsic oscillatory expression pattern was observed for some core clock components without any exogenous stimulation. The ZIKV infection significantly disturbed the mRNA expression pattern of core clock components in both neuroblastoma cell culture models, which was also observed in hiNPCs infected with different strains of ZIKV. The ZIKV-mediated desynchronization of the circadian clock expression in human cells might further contribute to the virus impairment of neuronal metabolism and function observed in adults and ZIKV-induced congenital syndrome. In vitro models of Zika virus (ZIKV) neuronal infection. Human neuroprogenitor cells were cultured as monolayer and neurospheres and infected by ZIKV. Monolayer-cultured cells received forskolin (FSK) as a coupling factor for the circadian clock rhythmicity, while 3D-arranged neurospheres showed an intrinsic oscillatory pattern in the circadian clock expression. The ZIKV infection affected the mRNA expression pattern of core clock components in both cell culture models. The ZIKV-mediated desynchronization of the circadian clock machinery might contribute to the impairment of neuronal metabolism and function observed in both adults (e.g., Guillain-Barré syndrome) and ZIKV-induced congenital syndrome (microcephaly). The graphical abstract has been created with Canva at the canva.com website.

Multimodal analysis of gene-expression patterns, electrophysiological properties, and morphological phenotypes at the single-cell/single-nucleus level has been arduous because of the diversity and complexity of neurons. The emergence of Patch-sequencing (Patch-seq) directly links transcriptomics, morphology, and electrophysiology, taking neuroscience research to a multimodal era. In this review, we summarized the development of Patch-seq and recent applications in the cortex, hippocampus, and other nervous systems. Through generating multimodal cell type atlases, targeting specific cell populations, and correlating transcriptomic data with phenotypic information, Patch-seq has provided new insight into outstanding questions in neuroscience. We highlight the challenges and opportunities of Patch-seq in neuroscience and hope to shed new light on future neuroscience research.

Lipid droplets (LDs) are subcellular organelles secreted from the endoplasmic reticulum (ER) that play a major role in lipid homeostasis. Recent research elucidates additional roles of LDs in cellular bioenergetics and innate immunity. LDs activate signaling cascades for interferon response and secretion of pro-inflammatory cytokines. Since balanced lipid homeostasis is critical for neuronal health, LDs play a crucial role in neurodegenerative diseases. RNA viruses enhance the secretion of LDs to support various phases of their life cycle in neurons which further leads to neurodegeneration. Targeting the excess LD formation in the brain could give us a new arsenal of antiviral therapeutics against neuroviruses. Liposomes are a suitable drug delivery system that could be used for drug delivery in the brain by crossing the Blood-Brain Barrier. Utilizing this, various pharmacological inhibitors and non-coding RNAs can be delivered that could inhibit the biogenesis of LDs or reduce their sizes, reversing the excess lipid-related imbalance in neurons. Liposome-Mediated Antiviral Drug Delivery Across Blood-Brain Barrier. Developing effective antiviral drug is challenging and it doubles against neuroviruses that needs delivery across the Blood-Brain Barrier (BBB). Lipid Droplets (LDs) are interesting targets for developing antivirals, hence targeting LD formation by drugs delivered using Liposomes can be game changers.

Stroke is the third leading cause of death and long-term disability in the world. Considered largely a disease of aging, its global economic and healthcare burden is expected to rise as more people survive into advanced age. With recent advances in acute stroke management, including the expansion of time windows for treatment with intravenous thrombolysis and mechanical thrombectomy, we are likely to see an increase in survival rates. It is therefore critically important to understand the complete pathophysiology of ischemic stroke, both in the acute and subacute stages and during the chronic phase in the months and years following an ischemic event. One of the most clinically relevant aspects of the chronic sequelae of stroke is its extended negative effect on cognition. Cognitive impairment may be related to the deterioration and dysfunctional reorganization of white matter seen at later timepoints after stroke, as well as ongoing progressive neurodegeneration. The vasculature of the brain also undergoes significant insult and remodeling following stroke, undergoing changes which may further contribute to chronic stroke pathology. While inflammation and the immune response are well established drivers of acute stroke pathology, the chronicity and functional role of innate and adaptive immune responses in the post-ischemic brain and in the peripheral environment remain largely uncharacterized. In this review, we summarize the current literature on post-stroke injury progression, its chronic pathological features, and the putative secondary injury mechanisms underlying the development of cognitive impairment and dementia. We present findings from clinical and experimental studies and discuss the long-term effects of ischemic stroke on both brain anatomy and functional outcome. Identifying mechanisms that occur months to years after injury could lead to treatment strategies in the chronic phase of stroke to help mitigate stroke-associated cognitive decline in patients.

Traumatic brain injury (TBI) is a serious public health problem worldwide, which could lead to an extremely high percentage of mortality and disability. Current treatment strategies mainly concentrate on neuronal protection and reconstruction, among them, exogenous neural stem cell (NSC) transplantation has long been regarded as the most effective curative treatment. However, due to secondary trauma, transplant rejection, and increased incidence of brain malignant tumor, a non-invasive therapy that enhanced endogenous neurogenesis was more suitable for TBI treatment. Our previous work has shown that miR-132 overexpression could improve neuronal differentiation of NSCs in vitro and in vivo. So, we engineered a new kind of AAV vector named AAV-PHP.eB which can transfect brain parenchyma through intravenous injection to overexpress miR-132 in brain after TBI. We found that miR-132 overexpression could reduce impact volume, promote neurogenesis in the dentate gyrus (DG), accelerate neuroblast migrating into the impact cortex, ameliorate microglia-mediated inflammatory reaction, and ultimately restore learning memory function. Our results revealed that AAV-PHP.eB-based miR-132 overexpression could improve endogenous tissue repairment and release clinical symptoms after traumatic brain injury. This work would provide a new therapeutic strategy for TBI treatment and other neurological disorders characterized by markable neuronal loss and memory impairment.

Graphical Abstract

miR-132 overexpression accelerates endogenous neurogenesis and releases TBI-induced tissue repairment and memory impairment. Controlled cortical impact onto the cortex would induce serious cortical injury and microglia accumulation in both cortex and hippocampus. Moreover, endogenous neuroblast could migrate around the injury core. miR-132 overexpression could accelerate neuroblast migration toward the injury core and decreased microglia accumulation in the ipsilateral cortex and hippocampus. miR-132 could be a suitable target on neuroprotective therapy after TBI.

Multiple sclerosis (MS) is a chronic and degrading autoimmune disorder mainly targeting the central nervous system, leading to progressive neurodegeneration, demyelination, and axonal damage. Current treatment options for MS are limited in efficacy, generally linked to adverse side effects, and do not offer a cure. Stem cell therapies have emerged as a promising therapeutic strategy for MS, potentially promoting remyelination, exerting immunomodulatory effects and protecting against neurodegeneration. Therefore, this review article focussed on the potential of nano-engineering in stem cells as a therapeutic approach for MS, focusing on the synergistic effects of combining stem cell biology with nanotechnology to stimulate the proliferation of oligodendrocytes (OLs) from neural stem cells and OL precursor cells, by manipulating neural signalling pathways-PDGF, BMP, Wnt, Notch and their essential genes such as Sox, bHLH, Nkx. Here we discuss the pathophysiology of MS, the use of various types of stem cells in MS treatment and their mechanisms of action. In the context of nanotechnology, we present an overview of its applications in the medical and research field and discuss different methods and materials used to nano-engineer stem cells, including surface modification, biomaterials and scaffolds, and nanoparticle-based delivery systems. We further elaborate on nano-engineered stem cell techniques, such as nano script, nano-exosome hybrid, nano-topography and their potentials in MS. The article also highlights enhanced homing, engraftment, and survival of nano-engineered stem cells, targeted and controlled release of therapeutic agents, and immunomodulatory and tissue repair effects with their challenges and limitations.

Graphical Abstract

This visual illustration depicts the process of utilizing nano-engineering in stem cells and exosomes for the purpose of delivering more accurate and improved treatments for Multiple Sclerosis (MS). This approach targets specifically the creation of oligodendrocytes, the breakdown of which is the primary pathological factor in MS.