Astrocytic heterogeneous nuclear ribonucleoprotein U facilitates scar formation after spinal cord injury
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA990796 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25118019_1.fastq.gz | Fastqsanger.gz | |||
| SRR25118019_2.fastq.gz | Fastqsanger.gz | |||
| SRR25118020_1.fastq.gz | Fastqsanger.gz | |||
| SRR25118020_2.fastq.gz | Fastqsanger.gz | |||
| SRR25118021_1.fastq.gz | Fastqsanger.gz |
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Project description:In this study, by a genome-wide RNA interference screen, we identified heterogeneous nuclear ribonucleoprotein U (Hnrnpu) as an endogenous key molecule in astrocyte activation. Inhibition of Hnrnpu in astrocytes impairs the formation of astrocytic glial scar, motor function recovery, and neuronal regeneration after spinal cord injury (SCI) in mice. Therefore, we then performed gene expression profiling analysis to evalute the function of HNRNPU in human astrocytes. Our findings uncover that modulation of endogenous astrocytic function through Hnrnpu would be a promising therapeutic avenue to restore neurological function after the injury.
2025-01-28 | GSE236433 | GEO
Project description:Astrocytes have a beneficial role in tissue repair after central nervous system (CNS) injury. Although astrocyte proliferation is activated in response to injury, the intracellular mechanisms of astrocyte proliferation during acute phase of injury are not fully clarified. In this study, by functionally screening the highly expressed genes in the pathological state of spinal astrocytes, heterogeneous nuclear ribonucleoprotein U (Hnrnpu) is identified as a potential endogenous molecule that regulates astrocyte proliferation and the following scar formation. Inhibition of Hnrnpu in astrocytes impairs the formation of astrocytic glial scar, motor function recovery, and neuronal regeneration after spinal cord injury (SCI) in mice. In human astrocytes, HNRNPU knockdown downregulates the genes related to the astrocyte functions in scar formation and neuronal regeneration. These findings uncover that modulation of endogenous astrocytic function would be a promising therapeutic avenue to restore neurological function after CNS injury.
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Project description:AimThis study investigated whether histamine could play a protective role in pathophysiological response of spinal cord injury (SCI) and regulate the glial scar formation.MethodsFunctional assessment and histological analyses were performed to investigate the effect of histamine after SCI. Histidine decarboxylase knockout (HDC(-/-)) mice were used to confirm the action of histamine. Selective antagonists for H1 and H2 receptors were utilized in vivo and in vitro to verify the functional properties of histamine on astrogliosis.ResultsThe local administration of histamine significantly attenuated the tissue damage and glial scar formation after SCI. In particular, the astrogliosis and neurocan expression found around the lesion were significantly suppressed by histamine. Immunofluorescent staining for neurofilament showed that histamine promoted axonal growth across the glial scar. The HDC(-/-) mice, lacking in endogenous histamine, showed lower behavior score, increased lesion size and astrogliosis, as compared with the wild types. The effect of histamine on locomotor recovery and reactive astrogliosis is reversed by H1 receptor antagonist but not H2 receptor antagonist.ConclusionsOur results indicate that histamine significantly improved the chronic locomotor recovery via attenuating astrogliosis after SCI by stimulating histamine H1 receptor. This study highlights a therapeutic potential of histamine and its related drugs for SCI.
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Project description:This study examines the molecular effects of surgical scar resection in complete chronic spinal cord injury (SCI) through RNA sequencing. Results show that scar resection alters gene expression, with downregulation of axonal growth inhibitors and upregulation of neuroprotective genes. Additionally, the application of a decellularized extracellular matrix (dECM) hydrogel as a scaffold promoted angiogenesis. Gene Ontology analysis indicated enrichment of immune-related processes, suggesting that scar resection improves the spinal cord microenvironment for neural repair. These findings indicate the potential of combining scar resection with scaffolding to support recovery after chronic complete SCI.
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Project description:Adult regeneration in spinal cord is poor in mammalian but remarkable in the neonatal mammals and some vertebrates, including fish and salamanders. Increasing evidences basis of this interspecies and ontogeny highlighted the pivotal roles of neuron extrinsic factors-the glial scar, which exert confusing inhibiting or promoting regeneration function, but the spatiotemporal ordering of cellular and molecular events that drive repair processes in scar formation remains poorly understood. Here, we firstly constructed tissue-wide gene expression measurements of mouse spinal cords over the course of scar formation using the spatial transcriptomics (ST) technology in Spinal cord injury (SCI) repair. We analyzed the transcriptomes of nearly 15449 spots from 32 samples and distinguished normal and damage response regions. Compared to histological changes, spatial mapping of differentiation transitions in spinal cord injury site delineated the possible trajectory between subpopulations of fibroblast, glia and immune cell more comprehensively and defined the extent of scar boundary and core more accurately. Locally, we identified gene expression gradients from leading edge to the core of scar areas that allow for re-understanding of the scar microenvironment and found some regulators in special cell types, such as Thbs1 and Col1a2 in macrophage, CD36 and Postn in fibroblast, Plxnb2 and Nxpe3 in microglia, Clu in astrocyte and CD74 in oligodendrocyte. Last, we profiled the bidirectional ligand-receptor interactions at the neighbor cluster boundary, contributing to maintain scar architecture during gliosis and fibrosis, and found GPR37L1_PSAP and GPR37_PSAP were top 2 enriched gene-pairs between microglia and fibroblast or microglia and astrocyte. Together, the establishment of these profiles firstly uncovered scar spatial heterogeneity and lineage trajectory, provide an unbiased view of scar and served as a valuable resource for CNS injury treatment.
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Project description:Deficiency of the Heterogeneous Nuclear Ribonucleoprotein U locus leads to delayed hindbrain neurogenesis
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Project description:Transcriptome analysis of total RNA samples from heart tissue of knockout mice Alternative splicing is the main mechanism to increase protein diversity from an mRNA. Heterogeneous ribonucleoprotein (hnRNP) family members are vital regulators of alternative splicing. The hnRNP A1 is the most well-known protein in this family, but its role in embryonic development is not well understood. We generated hnRNP A1 knockout mice to study the function of hnRNP A1 in vivo. The hnRNP A1-depleted mice showed embryonic lethality because of muscle developmental defects. In a previous study, cellular hnRNP A2/B1 was reported to be capable of compensating for the expression of hnRNP A1. However, this phenomenon did not occur in the hnRNP A1 heterozygous mice in vivo. We demonstrated that hnRNP A1 regulated muscle-related genes expression and alternative splicing. In summary, our data demonstrated that hnRNP A1 plays a critical role in embryonic muscle development. Understanding the effects of hnRNP A1 in vivo may help to define the function of hnRNP A1 in alternative splicing.
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Project description:The Heterogeneous Nuclear Ribonucleoprotein U (HNRNPU) is the Safeguard of Neural Stem Cell Viability
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Project description:After spinal cord injury, inflammatory reaction induces the aggregation of astrocytes to form a glial scar that eventually blocks axonal regeneration. Transcription factor CCAAT/enhancer-binding protein delta (C/EBPδ) is a regulatory protein of genes responsive to inflammatory factors, but its role in glial scar formation after spinal cord injury remains unknown. By using a model of moderate spinal cord contusion injury at the mid-thoracic level, we found that C/EBPδ was expressed mostly in the reactive astrocytes bordering the lesion in wild-type mice from 7 days after the injury. C/EBPδ-deficient mice showed reduced glial scar formation, more residual white matter, and better motor function recovery compared with wild-type mice 28 days after the injury. Upon interleukin (IL)-1β stimulation in vitro, the increased expression of C/EBPδ in reactive astrocytes inhibited RhoA expression and, subsequently, the ability of astrocyte migration. However, these reactive astrocytes also produced an increased amount of matrix metalloproteinase-3, which promoted the migration of non-IL-1β-treated, inactive astrocytes. Although the involvement of other non-astroglial C/EBPδ cannot be entirely excluded, our studies suggest that astrocytic C/EBPδ is integral to the inflammatory cascades leading to glial scar formation after spinal cord injury.
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