インサイト - Computational Biology - # Spatial Transcriptomics of Meningeal Inflammation in Multiple Sclerosis

Spatial Transcriptomics Reveals Variable Penetrance of Inflammatory Signatures from Meningeal Inflammation into Adjacent Brain Parenchyma

Q: What other spatial transcriptomic or imaging techniques could be used to further elucidate the relationship between meningeal inflammation and grey matter pathology in multiple sclerosis

To further elucidate the relationship between meningeal inflammation and grey matter pathology in multiple sclerosis, additional spatial transcriptomic or imaging techniques can be employed. One such technique is single-cell RNA sequencing (scRNA-seq), which can provide a more detailed understanding of the cellular composition and gene expression profiles within specific regions of interest. By analyzing individual cells, scRNA-seq can reveal the heterogeneity of cell types involved in the inflammatory response and their interactions in the context of meningeal inflammation and adjacent brain parenchyma. This approach can help identify specific cell populations driving the inflammatory processes and their impact on grey matter pathology. Another valuable technique is spatial proteomics, which can complement spatial transcriptomics by providing information on the protein expression patterns within the affected regions. By integrating spatial transcriptomic data with spatial proteomic data, researchers can gain a comprehensive understanding of the molecular mechanisms underlying the pathology. This multi-omics approach can reveal key signaling pathways, protein interactions, and post-translational modifications that contribute to the development of grey matter pathology in multiple sclerosis. Imaging techniques such as multiplex immunofluorescence staining can also be utilized to validate the spatial transcriptomic findings and visualize the distribution of specific cell types, proteins, and inflammatory markers within the tissue. By combining spatial transcriptomics with high-resolution imaging, researchers can create detailed spatial maps of the inflammatory response and its impact on the surrounding brain tissue, providing valuable insights into the pathogenesis of grey matter pathology in multiple sclerosis.

Q: How might the findings from this mouse model translate to the human disease, given differences in the spatial distribution and organization of meningeal inflammation

Translating the findings from the mouse model of meningeal inflammation to the human disease of multiple sclerosis requires careful consideration of the differences in spatial distribution and organization of meningeal inflammation between the two systems. While the mouse model provides valuable insights into the molecular pathways and cellular interactions involved in meningeal inflammation and its effects on the adjacent brain parenchyma, the spatial distribution of meningeal inflammation in humans may vary. Human studies using post-mortem brain tissue samples from individuals with multiple sclerosis can help validate the findings from the mouse model and provide insights into the relevance of specific inflammatory pathways in the human disease. Spatial transcriptomic analyses of human brain tissue can reveal the similarities and differences in gene expression patterns between meningeal inflammation, grey matter pathology, and adjacent brain regions. By comparing the spatial organization of inflammatory responses in mouse models and human samples, researchers can identify conserved pathways and potential therapeutic targets for addressing grey matter pathology in multiple sclerosis. Additionally, advanced imaging techniques such as high-resolution MRI, positron emission tomography (PET), and optical coherence tomography (OCT) can be used to visualize meningeal inflammation and grey matter pathology in living patients with multiple sclerosis. These imaging modalities can provide real-time information on the spatial distribution of inflammatory lesions, neuronal damage, and neurodegenerative processes, allowing for the monitoring of disease progression and treatment response in clinical settings.

Q: Could targeting the specific inflammatory pathways that show the deepest penetration into the brain parenchyma (e.g. antigen processing/presentation, complement signaling) represent a promising therapeutic strategy for addressing grey matter pathology in multiple sclerosis

Targeting the specific inflammatory pathways that show the deepest penetration into the brain parenchyma, such as antigen processing/presentation and complement signaling, represents a promising therapeutic strategy for addressing grey matter pathology in multiple sclerosis. The findings from the spatial transcriptomic analysis in the mouse model suggest that these pathways play a critical role in the pathogenesis of grey matter pathology and could serve as potential targets for therapeutic intervention. By modulating antigen processing/presentation pathways, such as inhibiting the expression of major histocompatibility complex (MHC) molecules or blocking co-stimulatory signals, it may be possible to reduce the activation of autoreactive T cells and the subsequent inflammatory response in the brain parenchyma. Similarly, targeting complement signaling pathways, which are involved in neuroinflammation and tissue damage, could help mitigate the deleterious effects of meningeal inflammation on grey matter integrity. Therapeutic approaches that specifically inhibit these pathways, either through small molecule inhibitors, monoclonal antibodies, or gene editing technologies, could be developed to selectively modulate the immune response in the CNS and prevent or reduce grey matter pathology in multiple sclerosis. Clinical trials targeting these pathways in patients with multiple sclerosis could provide valuable insights into the efficacy and safety of such interventions and their potential to improve clinical outcomes for individuals with the disease.

核心概念

Meningeal inflammation in multiple sclerosis is linked to cortical grey matter pathology, but the mechanisms are unclear. Spatial transcriptomics analysis in a mouse model reveals broad upregulation of inflammatory pathways at sites of meningeal inflammation, with variable penetrance of these signatures into the adjacent brain parenchyma.

要約

The authors performed MRI-guided spatial transcriptomics in a mouse model of autoimmune meningeal inflammation (SJL EAE) to characterize the transcriptional signature in areas of meningeal inflammation and the underlying brain parenchyma.

Key findings:

Broad upregulation of inflammatory signaling pathways, including TNF, JAK-STAT, and NF-κB, was observed at sites of meningeal inflammation.
Only a subset of these inflammatory pathways were active in the adjacent brain parenchyma, as revealed by sub-clustering analysis.
The subset of immune programs induced in the brain parenchyma included complement signaling and antigen processing/presentation.
Trajectory gene and gene set modeling analysis confirmed variable penetration of immune signatures originating from meningeal inflammation into the adjacent brain tissue.
RNAscope validation demonstrated exponential decreases in the density of cells expressing inflammatory transcripts (e.g. C3, B2m, Cd74) with increasing distance from the meningeal inflammation.

These findings provide insights into the spatial relationship between meningeal inflammation and the underlying brain parenchyma, highlighting candidate pathways that may contribute to grey matter pathology in multiple sclerosis.

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biorxiv.org

統計

Cluster 11, which represents the area of meningeal inflammation, contained 132 upregulated genes and 70 downregulated genes compared to other clusters.
The top upregulated genes in cluster 11 included Cd74, C3, and Gfap.

引用

"Meningeal inflammation is a recognized risk factor for cortical grey matter pathology which can result in disabling symptoms such as cognitive impairment and depression, but the mechanisms linking meningeal inflammation and grey matter pathology remain unclear."
"Trajectory gene and gene set modeling analysis confirmed variable penetration of immune signatures originating from meningeal inflammation into the adjacent brain tissue."

抽出されたキーインサイト

Spatial Transcriptomics of Meningeal Inflammation Reveals Variable Penetrance of Inflammatory Gene Signatures into Adjacent Brain Parenchyma

by Gadani,S., S... 場所 www.biorxiv.org 06-06-2023

https://www.biorxiv.org/content/10.1101/2023.06.02.543421v2

深掘り質問

What other spatial transcriptomic or imaging techniques could be used to further elucidate the relationship between meningeal inflammation and grey matter pathology in multiple sclerosis

To further elucidate the relationship between meningeal inflammation and grey matter pathology in multiple sclerosis, additional spatial transcriptomic or imaging techniques can be employed. One such technique is single-cell RNA sequencing (scRNA-seq), which can provide a more detailed understanding of the cellular composition and gene expression profiles within specific regions of interest. By analyzing individual cells, scRNA-seq can reveal the heterogeneity of cell types involved in the inflammatory response and their interactions in the context of meningeal inflammation and adjacent brain parenchyma. This approach can help identify specific cell populations driving the inflammatory processes and their impact on grey matter pathology.
Another valuable technique is spatial proteomics, which can complement spatial transcriptomics by providing information on the protein expression patterns within the affected regions. By integrating spatial transcriptomic data with spatial proteomic data, researchers can gain a comprehensive understanding of the molecular mechanisms underlying the pathology. This multi-omics approach can reveal key signaling pathways, protein interactions, and post-translational modifications that contribute to the development of grey matter pathology in multiple sclerosis.
Imaging techniques such as multiplex immunofluorescence staining can also be utilized to validate the spatial transcriptomic findings and visualize the distribution of specific cell types, proteins, and inflammatory markers within the tissue. By combining spatial transcriptomics with high-resolution imaging, researchers can create detailed spatial maps of the inflammatory response and its impact on the surrounding brain tissue, providing valuable insights into the pathogenesis of grey matter pathology in multiple sclerosis.

How might the findings from this mouse model translate to the human disease, given differences in the spatial distribution and organization of meningeal inflammation

Translating the findings from the mouse model of meningeal inflammation to the human disease of multiple sclerosis requires careful consideration of the differences in spatial distribution and organization of meningeal inflammation between the two systems. While the mouse model provides valuable insights into the molecular pathways and cellular interactions involved in meningeal inflammation and its effects on the adjacent brain parenchyma, the spatial distribution of meningeal inflammation in humans may vary.
Human studies using post-mortem brain tissue samples from individuals with multiple sclerosis can help validate the findings from the mouse model and provide insights into the relevance of specific inflammatory pathways in the human disease. Spatial transcriptomic analyses of human brain tissue can reveal the similarities and differences in gene expression patterns between meningeal inflammation, grey matter pathology, and adjacent brain regions. By comparing the spatial organization of inflammatory responses in mouse models and human samples, researchers can identify conserved pathways and potential therapeutic targets for addressing grey matter pathology in multiple sclerosis.
Additionally, advanced imaging techniques such as high-resolution MRI, positron emission tomography (PET), and optical coherence tomography (OCT) can be used to visualize meningeal inflammation and grey matter pathology in living patients with multiple sclerosis. These imaging modalities can provide real-time information on the spatial distribution of inflammatory lesions, neuronal damage, and neurodegenerative processes, allowing for the monitoring of disease progression and treatment response in clinical settings.

Could targeting the specific inflammatory pathways that show the deepest penetration into the brain parenchyma (e.g. antigen processing/presentation, complement signaling) represent a promising therapeutic strategy for addressing grey matter pathology in multiple sclerosis

Targeting the specific inflammatory pathways that show the deepest penetration into the brain parenchyma, such as antigen processing/presentation and complement signaling, represents a promising therapeutic strategy for addressing grey matter pathology in multiple sclerosis. The findings from the spatial transcriptomic analysis in the mouse model suggest that these pathways play a critical role in the pathogenesis of grey matter pathology and could serve as potential targets for therapeutic intervention.
By modulating antigen processing/presentation pathways, such as inhibiting the expression of major histocompatibility complex (MHC) molecules or blocking co-stimulatory signals, it may be possible to reduce the activation of autoreactive T cells and the subsequent inflammatory response in the brain parenchyma. Similarly, targeting complement signaling pathways, which are involved in neuroinflammation and tissue damage, could help mitigate the deleterious effects of meningeal inflammation on grey matter integrity.
Therapeutic approaches that specifically inhibit these pathways, either through small molecule inhibitors, monoclonal antibodies, or gene editing technologies, could be developed to selectively modulate the immune response in the CNS and prevent or reduce grey matter pathology in multiple sclerosis. Clinical trials targeting these pathways in patients with multiple sclerosis could provide valuable insights into the efficacy and safety of such interventions and their potential to improve clinical outcomes for individuals with the disease.