Reactive gliosis in traumatic brain injury: a comprehensive review

Frontiers in Cellular Neuroscience, Год журнала: 2024, Номер 18

Опубликована: Фев. 28, 2024

Traumatic brain injury (TBI) is one of the most common pathological conditions impacting central nervous system (CNS). A neurological deficit associated with TBI results from a complex pathogenetic mechanisms including glutamate excitotoxicity, inflammation, demyelination, programmed cell death, or development edema. The critical components contributing to CNS response, damage control, and regeneration after are glial cells–in reaction tissue damage, their activation, hypertrophy, proliferation occur, followed by formation scar. scar creates barrier in damaged helps protect acute phase post-injury. However, this process prevents complete recovery late/chronic producing permanent scarring, which significantly impacts function. Various types participate formation, but mostly attributed reactive astrocytes microglia, play important roles several pathologies. Novel technologies whole-genome transcriptomic epigenomic analyses, unbiased proteomics, show that both microglia represent groups heterogenic subpopulations different genomic functional characteristics, responsible for role neurodegeneration, neuroprotection regeneration. Depending on representation distinct glia subpopulations, as well regenerative processes delayed neurodegeneration may thus differ nearby remote areas structures. This review summarizes process, where resultant effect severity-, region- time-dependent determined model distance explored area lesion site. Here, we also discuss findings concerning intercellular signaling, long-term possibilities novel therapeutical approaches. We believe comprehensive study an emphasis cells, involved post-injury processes, be helpful further research decisive factor when choosing model.

Язык: Английский

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A single-cell atlas deconstructs heterogeneity across multiple models in murine traumatic brain injury and identifies novel cell-specific targets

Neuron, Год журнала: 2024, Номер 112(18), С. 3069 - 3088.e4

Опубликована: Июль 16, 2024

Traumatic brain injury (TBI) heterogeneity remains a critical barrier to translating therapies. Identifying final common pathways/molecular signatures that integrate this informs biomarker and therapeutic-target development. We present the first large-scale murine single-cell atlas of transcriptomic response TBI (334,376 cells) across clinically relevant models, sex, region, time as foundational step in molecularly deconstructing heterogeneity. Results were unique cell populations, regions, time, highlighting importance cell-level resolution. identify cell-specific targets previously unrecognized roles for microglial ependymal subtypes. Ependymal-4 was hub neuroinflammatory signaling. A distinct lineage shared features with disease-associated microglia at 24 h, persistent gene-expression changes microglia-4 even 6 months after contusional TBI, contrasting all other types mostly returned naive levels. Regional sexual dimorphism noted. CEREBRI, our searchable (https://shiny.crc.pitt.edu/cerebri/), identifies subtypes/molecular is leverageable platform future efforts diseases overlapping pathophysiology.

Язык: Английский

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Mgp High‐Expressing MSCs Orchestrate the Osteoimmune Microenvironment of Collagen/Nanohydroxyapatite‐Mediated Bone Regeneration

Advanced Science, Год журнала: 2024, Номер 11(23)

Опубликована: Апрель 8, 2024

Abstract Activating autologous stem cells after the implantation of biomaterials is an important process to initiate bone regeneration. Although several studies have demonstrated mechanism biomaterial‐mediated regeneration, a comprehensive single‐cell level transcriptomic map revealing influence on regulating temporal and spatial expression patterns mesenchymal (MSCs) still lacking. Herein, osteoimmune microenvironment depicted around classical collagen/nanohydroxyapatite‐based repair materials via combining analysis RNA sequencing transcriptomics. A group functional MSCs with high matrix Gla protein ( Mgp ) identified, which may serve as pioneer subpopulation involved in repair. Remarkably, these high‐expressing hi MSCs) exhibit efficient osteogenic differentiation potential orchestrate implanted biomaterials, rewiring polarization osteoclastic macrophages through Mdk/Lrp1 ligand–receptor pair. The inhibition activates pro‐inflammatory programs osteoclastogenesis. Meanwhile, multiple immune‐cell subsets also close crosstalk between secreted phosphoprotein 1 (SPP1) signaling pathway. These cellular profiles interactions characterized this study can broaden understanding MSC subpopulations at early stage regeneration provide basis for materials‐designed strategies that target modulation.

Язык: Английский

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High-altitude hypoxia aggravated neurological deficits in mice induced by traumatic brain injury via BACH1 mediating astrocytic ferroptosis

Cell Death Discovery, Год журнала: 2025, Номер 11(1)

Опубликована: Фев. 5, 2025

Abstract Traumatic brain injury (TBI) is one of the leading causes disability and mortality, which was classified as low-altitude TBI high-altitude TBI. A large amount literature shows that associated with more severe neurological impairments higher mortality rates compared to TBI, due special environment hypoxia. However, role hypoxia in pathogenesis remains unclear. In order deeply investigate this scientific issue, we constructed a hypoxic model at different altitudes used animal behavioral assessments (Modified severity score, rotarod test, elevated plus maze test) well histopathological analyses (brain gross specimens, water content, Evans blue inducible factor-1α, Hematoxylin-Eosin staining ROS detection) reveal its underlying principles characteristics. We found altitude, TBI-induced deficits were changes significant. Single-nuclear RNA sequencing subsequently employed further differential gene expression profiles significant increase ferroptosis astrocytes cases those Analyzing transcription factors depth, Bach1 plays crucial regulating key molecules induce following Down-regulation can effectively alleviate mice. conclusion, may significantly enhance aggravate by up-regulating expression. Our study provides theoretical foundation for understanding mechanism targeted intervention therapy.

Язык: Английский

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Single‐cell RNA‐sequencing analysis reveals enhanced non‐canonical neurotrophic factor signaling in the subacute phase of traumatic brain injury

CNS Neuroscience & Therapeutics, Год журнала: 2023, Номер 29(11), С. 3446 - 3459

Опубликована: Июнь 2, 2023

Traumatic brain injury (TBI) is a leading cause of long-term disability in young adults and induces complex neuropathological processes. Cellular autonomous intercellular changes during the subacute phase contribute substantially to neuropathology TBI. However, underlying mechanisms remain elusive. In this study, we explored dysregulated cellular signaling TBI.Single-cell RNA-sequencing data (GSE160763) TBI were analyzed explore cell-cell communication Upregulated neurotrophic factor was validated mouse model Primary cell cultures lines used as vitro models examine potential affecting signaling.Single-cell analysis revealed that microglia astrocytes most affected cells Cell-cell demonstrated mediated by non-canonical factors midkine (MDK), pleiotrophin (PTN), prosaposin (PSAP) microglia/astrocytes upregulated Time-course profiling showed MDK, PTN, PSAP expression primarily TBI, major source MDK PTN after studies enhanced activated microglia. Moreover, promoted proliferation neural progenitors derived from human-induced pluripotent stem (iPSCs) neurite growth iPSC-derived neurons, whereas exclusively stimulated growth.The played crucial role neuroregeneration.

Язык: Английский

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Thyroid hormone T4 mitigates traumatic brain injury in mice by dynamically remodeling cell type specific genes, pathways, and networks in hippocampus and frontal cortex

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Год журнала: 2024, Номер 1870(8), С. 167344 - 167344

Опубликована: Июль 14, 2024

The complex pathology of mild traumatic brain injury (mTBI) is a main contributor to the difficulties in achieving successful therapeutic regimen. Thyroxine (T4) administration has been shown prevent cognitive impairments induced by mTBI mice but mechanism poorly understood. To understand underlying mechanism, we carried out single cell transcriptomic study investigate spatiotemporal effects T4 on individual types hippocampus and frontal cortex at three post-injury stages mouse model mTBI. We found that treatment altered proportions transcriptomes numerous across tissues timepoints, particularly oligodendrocytes, astrocytes, microglia, which are crucial for repair. also reversed expression mTBI-affected genes such as Ttr, mt-Rnr2, Ggn12, Malat1, Gnaq, Myo3a, well pathways cell/energy/iron metabolism, immune response, nervous system, cytoskeleton-related pathways. Cell-type specific network modeling revealed mitigated select mTBI-perturbed dynamic shifts subnetworks related cycle, stress RNA processing oligodendrocytes. Cross cell-type ligand-receptor networks roles App, Hmgb1, Fn1, Tnf mTBI, with latter two ligands having previously identified TBI hubs. and/or signature were enriched human genome-wide association (GWAS) candidate cognitive, psychiatric neurodegenerative disorders Our systems-level analysis elucidated temporal spatial reprogramming genes, pathways, networks, cell-cell communications mechanisms through mitigates dysfunction

Язык: Английский

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Single-cell RNA sequencing in stroke and traumatic brain injury: Current achievements, challenges, and future perspectives on transcriptomic profiling

Journal of Cerebral Blood Flow & Metabolism, Год журнала: 2024, Номер unknown

Опубликована: Дек. 9, 2024

Single-cell RNA sequencing (scRNA-seq) is a high-throughput transcriptomic approach with the power to identify rare cells, discover new cellular subclusters, and describe novel genes. scRNA-seq can simultaneously reveal dynamic shifts in phenotypes heterogeneities subtypes. Since publication of first protocol on 2009, this evolving technology has continued improve, through use cell-specific barcodes, adoption droplet-based systems, development advanced computational methods. Despite induction stress response during tissue dissociation process, remains popular technology, commercially available methods have been applied brain. Recent advances spatial transcriptomics now allow researcher capture positional context transcriptional activity, strengthening our knowledge organization cell-cell interactions spatially intact tissues. A combination data proteomic, metabolomic, or chromatin accessibility promising direction for future research. Herein, we provide an overview workflow, analyses methods, pros cons technology. We also summarize latest achievements stroke acute traumatic brain injury, applications transcriptomics.

Язык: Английский

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The roles of pleiotrophin in brain injuries: a narrative review of the literature

Annals of Medicine, Год журнала: 2025, Номер 57(1)

Опубликована: Янв. 20, 2025

Background Pleiotrophin (PTN), a secreted multifunctional growth factor, is highly expressed in the developing brain. Recently, many studies have indicated that PTN participates development of brain and plays neuroprotection after injury, especially promoting neuronal survival neurite outgrowth, stimulating oligodendrocyte maturation myelination, modulating neuroinflammation, so on.

Язык: Английский

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Astrocytic pleiotrophin deficiency in the prefrontal cortex contributes to stress-induced depressive-like responses in male mice

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Март 14, 2025

Astrocytes are closely linked to depression, and the prefrontal cortex (PFC) is an important brain region involved in major depressive disorder (MDD). However, underlying mechanism by which astrocytes within PFC contribute MDD remains unclear. Using single-nucleus RNA sequencing analyses, we show a significant reduction attenuated pleiotrophin-protein tyrosine phosphatase receptor type Z1 (PTN-PTPRZ1) signaling astrocyte-to-excitatory neuron communication of male patients. We find reduced PTN dorsomedial mice with depression induced chronic restraint social defeat stress. Knockdown astrocytic induces depression-related responses, reversed exogenous supplementation or overexpression PTN. The antidepressant effects exerted require interaction PTPRZ1 excitatory neurons, PTN-PTPRZ1 activates AKT pathway regulate responses. Our findings indicate PTN-PTPRZ1-AKT may be potential therapeutic target for MDD. but mechanisms remain Here, authors that pleiotrophin contributes depression-like phenotype mice.

Язык: Английский

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Single cell RNA sequencing after moderate traumatic brain injury: effects of therapeutic hypothermia

Journal of Neuroinflammation, Год журнала: 2025, Номер 22(1)

Опубликована: Апрель 18, 2025

Traumatic brain injury (TBI) initiates a cascade of cellular and molecular events that promote acute long-term patterns neuronal, glial, vascular, synaptic vulnerability leading to lasting neurological deficits. These complex responses lead programmed cell death, diffuse axonal injury, increased blood-brain barrier disruption, neuroinflammation, reactive gliosis, each potential target for therapeutic interventions. Posttraumatic hypothermia (TH) has been reported be highly protective after spinal cord studies have investigated mechanisms underlying mild hypothermic protection while commonly assessing heterogenous populations. In this study we conducted single-cell RNA sequencing (scRNA-seq) on cerebral cortical tissues experimental TBI followed by period normothermia or comprehensively assess multiple type-specific transcriptional responses. C57BL/6 mice underwent moderate controlled impact (CCI) sham surgery then placed under sustained (37⁰C) (33⁰C) 2 h. After 24 h, including peri-contused regions were processed scRNA-seq. Unbiased clustering revealed heterogeneity among glial immune cells at subacute posttraumatic time point. The analysis also vascular subtypes associated with neovascularization debris clearance, respectively. Compared normothermic conditions, TH treatment altered the abundance specific induced astrocyte-specific modulation neurotropic factor gene expression. addition, an increase in proportion endothelial tip group was documented compared normothermia. data emphasize importance early temperature-sensitive processes producing potentially neuroprotective downstream signaling cascades cell-type-dependent manner. use scRNA-seq address treatments provides valuable resource identifying targetable biological pathways development reparative

Язык: Английский

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