-
Neuron Jul 2023Spinal cord injury (SCI) causes lifelong debilitating conditions. Previous works demonstrated the essential role of the immune system in recovery after SCI. Here, we...
Spinal cord injury (SCI) causes lifelong debilitating conditions. Previous works demonstrated the essential role of the immune system in recovery after SCI. Here, we explored the temporal changes of the response after SCI in young and aged mice in order to characterize multiple immune populations within the mammalian spinal cord. We revealed substantial infiltration of myeloid cells to the spinal cord in young animals, accompanied by changes in the activation state of microglia. In contrast, both processes were blunted in aged mice. Interestingly, we discovered the formation of meningeal lymphatic structures above the lesion site, and their role has not been examined after contusive injury. Our transcriptomic data predicted lymphangiogenic signaling between myeloid cells in the spinal cord and lymphatic endothelial cells (LECs) in the meninges after SCI. Together, our findings delineate how aging affects the immune response following SCI and highlight the participation of the spinal cord meninges in supporting vascular repair.
Topics: Mice; Animals; Endothelial Cells; Spinal Cord Injuries; Spinal Cord; Microglia; Myeloid Cells; Mammals
PubMed: 37148871
DOI: 10.1016/j.neuron.2023.04.011 -
Trends in Neurosciences Jul 2023Microglia play pivotal roles in controlling CNS functions in diverse physiological and pathological contexts, including neuropathic pain, a chronic pain condition caused... (Review)
Review
Microglia play pivotal roles in controlling CNS functions in diverse physiological and pathological contexts, including neuropathic pain, a chronic pain condition caused by lesions or diseases of the somatosensory nervous system. In this review article, we summarize evidence primarily from basic research on the role of microglia in the development and remission of neuropathic pain. The identification of a subset of microglia that emerged after pain development and that was necessary for remission of neuropathic pain highlights the highly divergent and dynamic nature of microglia in the course of neuropathic pain. Understanding microglial diversity in terms of gene expression, physiological states, and functional roles could lead to new strategies that aid in the diagnosis and management of neuropathic pain, and that may not have been anticipated from the viewpoint of targeting all microglia uniformly.
Topics: Humans; Microglia; Spinal Cord; Neuralgia; Chronic Disease
PubMed: 37244781
DOI: 10.1016/j.tins.2023.05.001 -
Nature Dec 2023Ageing is a critical factor in spinal-cord-associated disorders, yet the ageing-specific mechanisms underlying this relationship remain poorly understood. Here, to...
Ageing is a critical factor in spinal-cord-associated disorders, yet the ageing-specific mechanisms underlying this relationship remain poorly understood. Here, to address this knowledge gap, we combined single-nucleus RNA-sequencing analysis with behavioural and neurophysiological analysis in non-human primates (NHPs). We identified motor neuron senescence and neuroinflammation with microglial hyperactivation as intertwined hallmarks of spinal cord ageing. As an underlying mechanism, we identified a neurotoxic microglial state demarcated by elevated expression of CHIT1 (a secreted mammalian chitinase) specific to the aged spinal cords in NHP and human biopsies. In the aged spinal cord, CHIT1-positive microglia preferentially localize around motor neurons, and they have the ability to trigger senescence, partly by activating SMAD signalling. We further validated the driving role of secreted CHIT1 on MN senescence using multimodal experiments both in vivo, using the NHP spinal cord as a model, and in vitro, using a sophisticated system modelling the human motor-neuron-microenvironment interplay. Moreover, we demonstrated that ascorbic acid, a geroprotective compound, counteracted the pro-senescent effect of CHIT1 and mitigated motor neuron senescence in aged monkeys. Our findings provide the single-cell resolution cellular and molecular landscape of the aged primate spinal cord and identify a new biomarker and intervention target for spinal cord degeneration.
Topics: Animals; Humans; Biomarkers; Cellular Senescence; Chitinases; Microglia; Motor Neurons; Neuroinflammatory Diseases; Primates; Reproducibility of Results; Single-Cell Gene Expression Analysis; Spinal Cord
PubMed: 37907096
DOI: 10.1038/s41586-023-06783-1 -
Continuum (Minneapolis, Minn.) Feb 2024Vascular injuries of the spinal cord are less common than those involving the brain; however, they can be equally devastating. This article discusses the diagnosis and...
OBJECTIVE
Vascular injuries of the spinal cord are less common than those involving the brain; however, they can be equally devastating. This article discusses the diagnosis and management of ischemic and hemorrhagic vascular disorders of the spinal cord.
LATEST DEVELOPMENTS
Clinical suspicion remains the mainstay for recognizing vascular myelopathies, yet diagnoses are often delayed and challenging in part because of their rarity and atypical manifestations. Noninvasive imaging such as CT and MRI continues to improve in spatial resolution and diagnostic precision; however, catheter-based spinal angiography remains the gold standard for defining the spinal angioarchitecture. In addition to hemorrhagic and ischemic disease, the contribution of venous dysfunction is increasingly appreciated and informs treatment strategies in conditions such as intracranial hypotension.
ESSENTIAL POINTS
Vascular disorders of the spine manifest in variable and often atypical ways, which may lead to delayed diagnosis. Increased awareness of these conditions is critical for early recognition and treatment. The goal of treatment is to minimize long-term morbidity and mortality.
Topics: Humans; Spinal Cord; Vascular Diseases; Spinal Cord Diseases; Spine; Magnetic Resonance Imaging
PubMed: 38330477
DOI: 10.1212/CON.0000000000001378 -
Nature Dec 2023The brain controls nearly all bodily functions via spinal projecting neurons (SPNs) that carry command signals from the brain to the spinal cord. However, a...
The brain controls nearly all bodily functions via spinal projecting neurons (SPNs) that carry command signals from the brain to the spinal cord. However, a comprehensive molecular characterization of brain-wide SPNs is still lacking. Here we transcriptionally profiled a total of 65,002 SPNs, identified 76 region-specific SPN types, and mapped these types into a companion atlas of the whole mouse brain. This taxonomy reveals a three-component organization of SPNs: (1) molecularly homogeneous excitatory SPNs from the cortex, red nucleus and cerebellum with somatotopic spinal terminations suitable for point-to-point communication; (2) heterogeneous populations in the reticular formation with broad spinal termination patterns, suitable for relaying commands related to the activities of the entire spinal cord; and (3) modulatory neurons expressing slow-acting neurotransmitters and/or neuropeptides in the hypothalamus, midbrain and reticular formation for 'gain setting' of brain-spinal signals. In addition, this atlas revealed a LIM homeobox transcription factor code that parcellates the reticulospinal neurons into five molecularly distinct and spatially segregated populations. Finally, we found transcriptional signatures of a subset of SPNs with large soma size and correlated these with fast-firing electrophysiological properties. Together, this study establishes a comprehensive taxonomy of brain-wide SPNs and provides insight into the functional organization of SPNs in mediating brain control of bodily functions.
Topics: Animals; Mice; Gene Expression Profiling; Hypothalamus; Neurons; Neuropeptides; Spinal Cord; Brain; Neural Pathways; Neurotransmitter Agents; Mesencephalon; Reticular Formation; Electrophysiology; Cerebellum; Cerebral Cortex
PubMed: 38092914
DOI: 10.1038/s41586-023-06817-8 -
International Journal of Biological... 2023The JAK/STAT signaling pathway is the main inflammatory signal transduction pathway, whether JAK/STAT contributes the pathology of SCI and targeting the pathway will...
The JAK/STAT signaling pathway is the main inflammatory signal transduction pathway, whether JAK/STAT contributes the pathology of SCI and targeting the pathway will alleviate SCI needs to be addressed. Here, we explored the therapeutic effect of pan-JAK inhibitor tofacitinib (TOF) on secondary injury after SCI and explained the underlying mechanisms. SCI model in rat was established to evaluate the therapeutic effects of TOF treatment . Histological and behavioral analyses were performed at different time points after SCI. , the effects of TOF on pro-inflammatory activation of primary microglia and BV2 cells were analyzed by western blot analysis, fluorescent staining, qPCR and flow cytometry. The neuroprotection of TOF was detected using a co-culture system with primary neurons and microglia. TOF can effectively improve motor dysfunction caused by spinal cord injury in rats. TOF administration in the early stage of inflammation can effectively inhibit neuronal apoptosis and scar tissue formation, and promote the repair of axons and nerve fibers. Further studies have demonstrated that TOF suppresses inflammation caused by spinal cord injury by inhibiting the activation of microglia to pro-inflammatory phenotype and . Additionally, an interesting phenomenon is revealed in our results that TOF exhibits superior neuronal protection during inflammation . Our study showed that TOF could regulate microglial activation via JAK / STAT pathway and promote the recovery of motor function after SCI, which is of great significance for the immunotherapy of SCI.
Topics: Rats; Animals; Microglia; Rats, Sprague-Dawley; Spinal Cord Injuries; Inflammation; Signal Transduction; Spinal Cord
PubMed: 37781508
DOI: 10.7150/ijbs.84564 -
Nature Communications Jul 2023The transplantation of mesenchymal stem cells-derived secretome, particularly extracellular vesicles is a promising therapy to suppress spinal cord injury-triggered...
The transplantation of mesenchymal stem cells-derived secretome, particularly extracellular vesicles is a promising therapy to suppress spinal cord injury-triggered neuroinflammation. However, efficient delivery of extracellular vesicles to the injured spinal cord, with minimal damage, remains a challenge. Here we present a device for the delivery of extracellular vesicles to treat spinal cord injury. We show that the device incorporating mesenchymal stem cells and porous microneedles enables the delivery of extracellular vesicles. We demonstrate that topical application to the spinal cord lesion beneath the spinal dura, does not damage the lesion. We evaluate the efficacy of our device in a contusive spinal cord injury model and find that it reduces the cavity and scar tissue formation, promotes angiogenesis, and improves survival of nearby tissues and axons. Importantly, the sustained delivery of extracellular vesicles for at least 7 days results in significant functional recovery. Thus, our device provides an efficient and sustained extracellular vesicles delivery platform for spinal cord injury treatment.
Topics: Humans; Porosity; Spinal Cord Injuries; Spinal Cord; Axons; Extracellular Vesicles
PubMed: 37419902
DOI: 10.1038/s41467-023-39745-2 -
Nature Communications Aug 2023Spinal cord injury (SCI) leads to severe sensory and motor dysfunction below the lesion. However, the cellular dynamic responses and heterogeneity across different...
Spinal cord injury (SCI) leads to severe sensory and motor dysfunction below the lesion. However, the cellular dynamic responses and heterogeneity across different regions below the lesion remain to be elusive. Here, we used single-cell transcriptomics to investigate the region-related cellular responses in female rhesus monkeys with complete thoracic SCI from acute to chronic phases. We found that distal lumbar tissue cells were severely impacted, leading to degenerative microenvironments characterized by disease-associated microglia and oligodendrocytes activation alongside increased inhibitory interneurons proportion following SCI. By implanting scaffold into the injury sites, we could improve the injury microenvironment through glial cells and fibroblast regulation while remodeling spared lumbar tissues via reduced inhibitory neurons proportion and improved phagocytosis and myelination. Our findings offer crucial pathological insights into the spared distal tissues and proximal tissues after SCI, emphasizing the importance of scaffold-based treatment approaches targeting heterogeneous microenvironments.
Topics: Animals; Female; Macaca mulatta; Spinal Cord; Spinal Cord Injuries; Neuroglia; Single-Cell Analysis
PubMed: 37558705
DOI: 10.1038/s41467-023-40513-5 -
CNS Neuroscience & Therapeutics Jul 2023Spinal cord injury (SCI) is a highly disabling condition in spinal surgery that leads to neuronal damage and secondary inflammation. Ferroptosis is a non-apoptotic type...
BACKGROUND
Spinal cord injury (SCI) is a highly disabling condition in spinal surgery that leads to neuronal damage and secondary inflammation. Ferroptosis is a non-apoptotic type of cell death that has only recently been identified, which is marked primarily by iron-dependent and lipid-derived reactive oxygen species accumulation, and accompanied by morphological modifications such as mitochondrial atrophy and increase in membrane density. Dihydroorotate dehydrogenase (DHODH) is a powerful inhibitor of ferroptosis and has been demonstrated to inhibit cellular ferroptosis in tumor cells, but whether it can inhibit neuronal injury following spinal cord injury remains ambiguous.
METHODS
In this study, the effect of DHODH on neuronal ferroptosis was observed in vivo and in vitro using a rat spinal cord injury model and erastin-induced PC12 cells, respectively. A combination of molecular and histological approaches was performed to assess ferroptosis and explore the possible mechanisms in vivo and in vitro.
RESULTS
First, we confirmed the existence of neuronal ferroptosis after spinal cord injury and that DHODH attenuates neuronal damage after spinal cord injury. Second, we showed molecular evidence that DHODH inhibits the activation of ferroptosis-related molecules and reduces lipid peroxide production and mitochondrial damage, thereby reducing neuronal ferroptosis. Further analysis suggests that P53/ALOX15 may be one of the mechanisms regulated by DHODH. Importantly, we determined that DHODH inhibits ALOX15 expression by inhibiting P53.
CONCLUSIONS
Our findings reveal a novel function for DHODH in neuronal ferroptosis after spinal cord injury, suggesting a unique therapeutic target to alleviate the disease process of spinal cord injury.
Topics: Animals; Rats; Dihydroorotate Dehydrogenase; Ferroptosis; Neurons; Signal Transduction; Spinal Cord; Spinal Cord Injuries; Tumor Suppressor Protein p53
PubMed: 36942513
DOI: 10.1111/cns.14150 -
Nature Oct 2023Spatially charting molecular cell types at single-cell resolution across the 3D volume is critical for illustrating the molecular basis of brain anatomy and functions....
Spatially charting molecular cell types at single-cell resolution across the 3D volume is critical for illustrating the molecular basis of brain anatomy and functions. Single-cell RNA sequencing has profiled molecular cell types in the mouse brain, but cannot capture their spatial organization. Here we used an in situ sequencing method, STARmap PLUS, to profile 1,022 genes in 3D at a voxel size of 194 × 194 × 345 nm, mapping 1.09 million high-quality cells across the adult mouse brain and spinal cord. We developed computational pipelines to segment, cluster and annotate 230 molecular cell types by single-cell gene expression and 106 molecular tissue regions by spatial niche gene expression. Joint analysis of molecular cell types and molecular tissue regions enabled a systematic molecular spatial cell-type nomenclature and identification of tissue architectures that were undefined in established brain anatomy. To create a transcriptome-wide spatial atlas, we integrated STARmap PLUS measurements with a published single-cell RNA-sequencing atlas, imputing single-cell expression profiles of 11,844 genes. Finally, we delineated viral tropisms of a brain-wide transgene delivery tool, AAV-PHP.eB. Together, this annotated dataset provides a single-cell resource that integrates the molecular spatial atlas, brain anatomy and the accessibility to genetic manipulation of the mammalian central nervous system.
Topics: Animals; Mice; Brain; Central Nervous System; Single-Cell Analysis; Spinal Cord; Transcriptome; Single-Cell Gene Expression Analysis; Viral Tropism; Datasets as Topic; Transgenes; Imaging, Three-Dimensional
PubMed: 37758947
DOI: 10.1038/s41586-023-06569-5