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Engineered T cell therapy for central nervous system injury [CSF RNAseq + VDJ]

ABSTRACT: Traumatic injuries to the central nervous system (CNS) affect millions of people worldwide yet lack an effective treatment. These injuries contain infiltrating immune cells that can promote tissue repair and could be exploited for therapeutic benefit. Here, using single-cell RNA-sequencing of T cells infiltrating the injured CNS we demonstrate their clonal expansion and antigen specificity towards CNS derived self-peptides. We confirm the beneficial effect of these injury-associated autoimmune CD4+ T cells in murine models of optic nerve and spinal cord injury. Subsequently, using mRNA-based transient T cell receptor (TCR) reconstitution, we demonstrate a therapeutic T cell strategy to alleviate CNS injury. Treatment of CNS-injured mice with this therapy improved locomotion and alleviated histological signs of damage, through regulation of myeloid cells, without detrimental autoimmune side effects. This strategy provides a means of developing custom-designed T cell therapies for CNS injury, and possibly for other neurodegenerative disorders.

ORGANISM(S): Homo sapiens

PROVIDER: GSE273504 | GEO | 2024/07/31

REPOSITORIES: GEO

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Engineered T cell therapy for central nervous system injury [FACS-Tcells]

Project description:Traumatic injuries to the central nervous system (CNS) affect millions of people worldwide yet lack an effective treatment. These injuries contain infiltrating immune cells that can promote tissue repair and could be exploited for therapeutic benefit. Here, using single-cell RNA-sequencing of T cells infiltrating the injured CNS we demonstrate their clonal expansion and antigen specificity towards CNS derived self-peptides. We confirm the beneficial effect of these injury-associated autoimmune CD4+ T cells in murine models of optic nerve and spinal cord injury. Subsequently, using mRNA-based transient T cell receptor (TCR) reconstitution, we demonstrate a therapeutic T cell strategy to alleviate CNS injury. Treatment of CNS-injured mice with this therapy improved locomotion and alleviated histological signs of damage, through regulation of myeloid cells, without detrimental autoimmune side effects. This strategy provides a means of developing custom-designed T cell therapies for CNS injury, and possibly for other neurodegenerative disorders.

2024-07-23 | GSE216388 | GEO

Engineered T cell therapy for central nervous system injury [control tissues TCR scRNA-seq]

2024-07-23 | GSE189812 | GEO

Engineered T cell therapy for central nervous system injury [spinal cord TCR scRNA-seq]

2024-07-23 | GSE216390 | GEO

Engineered T cell therapy for central nervous system injury [CD45+ scRNA-seq]

2024-07-23 | GSE216389 | GEO

Effect of peripherally-derived macrophages in adult microglia (mouse cells)

Project description:Infiltrating monocyte derived macrophages (MDMs) and resident microglia dominate CNS injury sites. We show that MDMs and microglia can directly communicate to modulate each other’s function. Also, the presence of MDMs in CNS injury suppresses microglia-mediated phagocytosis and inflammation. We suggest that macrophages infiltrating the injured CNS provide a mechanism to control acute and chronic microglia-mediated inflammation, which could otherwise drive damage in a variety of CNS conditions. To understand the global effects of macrophage communication to microglia, we transcriptionally profiled activated adult mouse microglia in the presence or absence of macrophages with and without an inflammatory stiumulus (LPS)

2018-08-01 | GSE102482 | GEO

Signatures of inflammation and impending multiple organ dysfunction in the hyperacute phase of trauma: A prospective cohort study

Project description:We performed whole blood transcriptome analysis on a total of 70 critically injured patients (Injury Severity Score [ISS] >25) in the hyperacute time period within 2 hours of injury, at 24h and again at 72h. We compared transcriptome findings in 36 critically injured patients with those of 6 patients with minor injuries (ISS < 4). Immediately after injury, only 1,239 gene transcripts (4%) were differentially expressed in critically injured patients. By 24 hours after injury, 6,294 transcripts (21%) were differentially expressed compared to the hyperacute window. Only 202 (16%) genes differentially expressed in the hyperacute window were still expressed in the same direction at 24 hours post injury.

2017-07-06 | E-MTAB-5882 | biostudies-arrayexpress

Expression data from reactive astrocytes acutely purified from young adult mouse brains

Project description:Reactive astrogliosis is characterized by a profound change in astrocyte phenotype in response to all CNS injuries and diseases. To better understand the reactive astrocyte state, we used Affymetrix GeneChip arrays to profile gene expression in populations of reactive astrocytes isolated at various time points after induction using two different mouse injury models, ischemic stroke and neuroinflammation. Young adult male mice underwent middle cerebral artery occlusion (MCAO) to produce ischemic stroke or control sham surgery. Young adult mice were injected intraperitoneally with 5 mg/kg lipopolysaccharide (LPS) to produce neuroinflammation or saline for control. Astrocytes were acutely purified from control and injured brains at 1 day after injury for LPS/saline injection and 1, 3 days and 7 days after MCAO/sham surgeries.

2012-05-01 | E-GEOD-35338 | biostudies-arrayexpress

A latent lineage potential in resident neural stem cells

Project description:Injuries to the central nervous system (CNS) are inefficiently repaired. Resident neural stem cells exist, but manifest a very limited contribution to cell replacement. Here we uncover a latent potential in neural stem cells to replace large numbers of oligodendrocytes in the injured mouse spinal cord. Using single cell genomics we found that neural stem cells are in a permissive chromatin state that enables the unfolding of a normally latent gene expression program for oligodendrogenesis after injury. Once unveiled, stem cell-derived oligodendrogenesis is abundant, follows the natural progression of oligodendrocyte differentiation, contributes to axon remyelination and stimulates functional recovery of axon conduction. Resident stem cells can thus serve as a meaningful reservoir for cellular replacement and constitute an alternative to cell transplantation after CNS injury.

2020-08-31 | GSE148316 | GEO

Gene expression in experimentally injured and control mouse spinal cords

Project description:This laboratory works on selectins and their carbohydrate ligands in lymphocyte homing and inflammation. The lab also studies heparin-degrading endosulfatases and their roles in regulating the interactions of growth factors and morphogens with proteoglycans. The purpose of the experiment is to examine gene expression profiles in spinal cords of injured as a function of time after a contusion injury. The tissue will be generated in the lab of Linda Noble, Professor in the Department of Neurological Surgery at UCSF who is an expert on the pathogenesis of spinal cord injury. Wild-type male C57B/6 mice (8-10 weeks of age) were used. Injuries were produced by contusion. Spinal cords from control mice (uninjured) and experimental (injured) mice were processed (4 and 7 days after injury). A 3 mm length of spinal cord (centered at the injury) and a 3 mm segment from a distant site were isolated from each animal. Tissue from 3 mice were pooled for each sample. Three replicate samples per treatment group were processed for RNA. Thus, a total of 18 RNA samples were hybridized to 18 gene chips. The analysis will determine whether specific glycosylation changes accompany spinal cord injury. Of particular interest are changes in the sulfation profile of proteoglycan GAG chains (e.g., chondroitin sulfate) and in the appearance of potential carbohydrate ligands for infiltrating leukocytes bearing L-selectin or other endogenous lectins.

2011-02-17 | E-GEOD-27359 | biostudies-arrayexpress

Exploring Relevant mRNAs and miRNAs in Injured Urethral Tissues of Rats with High-Throughput Sequencing [miRNA-seq]

Project description:Acute urethral injuries caused by urethral endoscopy and other mechanical injuries are the main reasons for secondary infection and late urethral stricture. However, there are no studies to explore the transcriptomic changes in urethral injury and the molecular mechanism of urethral injury, which is important for the treatment and cure of urethral injury. Therefore, we used RNA-seq and sRNA-seq profiles from normal and injured urethral tissues to identify and characterize differentially expressed mRNAs and miRNAs. In total, we found 166 differentially expressed mRNAs, of which 69 were upregulated, and 97 were downregulated in injured urethral tissues. The differentially expressed mRNAs were mainly involved in the positive regulation of epithelial cell differentiation, focal adhesion, cell adhesion molecules, protein activation cascade, complement activation, complement and coagulation cascades, and chemokine-mediated signaling pathway. Additionally, we found six upregulated and four downregulated miRNAs, respectively, in the injured urethral tissues. Notably, their target genes were involved in the vascular endothelial growth factor receptor 2 binding, PI3k-Akt signaling pathway, and Notch signaling pathway. In summary, our results suggest that the cell damage response induced by mechanical injury activates the pathological immune response in a variety of ways in injured urethral tissues.

2022-05-31 | GSE182947 | GEO

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