Browse
Submit Data
Databases
API
Help

Dataset Information

10 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Spinal Cord Injury Induces Permanent Reprogramming of Microglia into a Disease-Associated State Which Contributes to Functional Recovery.

ABSTRACT: Microglia are resident myeloid cells of the CNS. Recently, single-cell RNA sequencing (scRNAseq) has enabled description of a disease-associated microglia (DAM) with a role in neurodegeneration and demyelination. In this study, we use scRNAseq to investigate the temporal dynamics of immune cells harvested from the epicenter of traumatic spinal cord injury (SCI) induced in female mice. We find that as a consequence of SCI, baseline microglia undergo permanent transcriptional reprogramming into a previously uncharacterized subtype of microglia with striking similarities to previously reported DAM as well as a distinct microglial state found during development. Using a microglia depletion model we showed that DAM in SCI are derived from baseline microglia and strongly enhance recovery of hindlimb locomotor function following injury.SIGNIFICANCE STATEMENT Although disease-associated microglia (DAM) have been the subject of strong research interest during recent years (Keren-Shaul, 2017; Jordão, 2019), their cellular origin and their role in "normal" acute injury processes is not well understood. Our work directly addresses the origin and the role of DAM in traumatic injury response. Further, we use a microglia depletion model to prove that DAM in spinal cord injury (SCI) are indeed derived from homeostatic microglia, and that they strongly enhance recovery. Thus, in this work we significantly expand the knowledge of immune response to traumatic injury, demonstrate the applicability to human injury via our unique access to injured human spinal cord tissue, and provide the community with a comprehensive dataset for further exploration.

SUBMITTER: Hakim R

PROVIDER: S-EPMC8496189 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Gramine promotes functional recovery after spinal cord injury via ameliorating microglia activation.

Project description:In recent years, a large number of studies have reported that neuroinflammation aggravates the occurrence of secondary injury after spinal cord injury. Gramine (GM), a natural indole alkaloid, possesses various pharmacological properties; however, the anti-inflammation property remains unclear. In our study, Gramine was investigated in vitro and in vivo to explore the neuroprotection effects. In vitro experiment, our results suggest that Gramine treatment can inhibit release of pro-inflammatory mediators. Moreover, Gramine prevented apoptosis of PC12 cells which was caused by activated HAPI microglia, and the inflammatory secretion ability of microglia was inhibited by Gramine through NF-κB pathway. The in vivo experiment is that 80 mg/kg Gramine was injected orthotopically to rats after spinal cord injury (SCI). Behavioural and histological analyses demonstrated that Gramine treatment may alleviate microglia activation and then boost recovery of motor function after SCI. Overall, our research has demonstrated that Gramine exerts suppressed microglia activation and promotes motor functional recovery after SCI through NF-κB pathway, which may put forward the prospect of clinical treatment of inflammation-related central nervous diseases.

| S-EPMC8358888 | biostudies-literature

NG2 glia reprogramming induces robust axonal regeneration after spinal cord injury.

Project description:Spinal cord injury (SCI) often leads to neuronal loss, axonal degeneration, and behavioral dysfunction. We recently show that in vivo reprogramming of NG2 glia produces new neurons, reduces glial scaring, and ultimately leads to improved function after SCI. By examining endogenous neurons, we here unexpectedly uncover that NG2 glia reprogramming also induces robust axonal regeneration of the corticospinal tract and serotonergic neurons. Such reprogramming-induced axonal regeneration may contribute to the reconstruction of neural networks essential for behavioral recovery.

| S-EPMC10839253 | biostudies-literature

NG2 Glia Reprogramming Induces Robust Axonal Regeneration After Spinal Cord Injury.

Project description:Spinal cord injury (SCI) often leads to neuronal loss, axonal degeneration and behavioral dysfunction. We recently show that in vivo reprogramming of NG2 glia produces new neurons, reduces glial scaring, and ultimately leads to improved function after SCI. By examining endogenous neurons, we here unexpectedly uncover that NG2 glia reprogramming also induces robust axonal regeneration of the corticospinal tract and serotonergic neurons. Such reprogramming-induced axonal regeneration may contribute to the reconstruction of neural networks essential for behavioral recovery.

| S-EPMC10312714 | biostudies-literature

Depletion of microglia exacerbates injury and impairs function recovery after spinal cord injury in mice.

Project description:The role of microglia in spinal cord injury (SCI) remains ambiguous, partially due to the paucity of efficient methods to discriminate these resident microglia with blood-derived monocytes/macrophages. Here, we used pharmacological treatments to specifically eliminate microglia and subsequently to investigate the response of microglia after SCI in mice. We showed that treatment with colony stimulating factor 1 receptor (CSF1R) inhibitor PLX3397 eliminated ~90% microglia and did not affect other cell types in mouse spinal cord. PLX3397 treatment also induced a strong decrease in microglial proliferation induced by SCI. Depletion of microglia after SCI disrupted glial scar formation, enhanced immune cell infiltrates, reduced neuronal survival, delayed astrocyte repopulation, exacerbated axonal dieback, and impaired locomotor recovery. Therefore, our findings suggest microglia may play a protective role after SCI in mice.

| S-EPMC7359318 | biostudies-literature

Inhibiting microglia proliferation after spinal cord injury improves recovery in mice and nonhuman primates.

Project description:No curative treatment is available for any deficits induced by spinal cord injury (SCI). Following injury, microglia undergo highly diverse activation processes, including proliferation, and play a critical role on functional recovery. In a translational objective, we investigated whether a transient pharmacological reduction of microglia proliferation after injury is beneficial for functional recovery after SCI in mice and nonhuman primates. Methods: The colony stimulating factor-1 receptor (CSF1R) regulates proliferation, differentiation, and survival of microglia. We orally administrated GW2580, a CSF1R inhibitor that inhibits microglia proliferation. In mice and nonhuman primates, we then analyzed treatment outcomes on locomotor function and spinal cord pathology. Finally, we used cell-specific transcriptomic analysis to uncover GW2580-induced molecular changes in microglia. Results: First, transient post-injury GW2580 administration in mice improves motor function recovery, promotes tissue preservation and/or reorganization (identified by coherent anti-stokes Raman scattering microscopy), and modulates glial reactivity. Second, post-injury GW2580-treatment in nonhuman primates reduces microglia proliferation, improves motor function recovery, and promotes tissue protection. Finally, GW2580-treatment in mice induced down-regulation of proliferation-associated transcripts and inflammatory associated genes in microglia that may account for reduced neuroinflammation and improved functional recovery following SCI. Conclusion: Thus, a transient oral GW2580 treatment post-injury may provide a promising therapeutic strategy for SCI patients and may also be extended to other central nervous system disorders displaying microglia activation.

| S-EPMC8419033 | biostudies-literature

Salidroside attenuates neuroinflammation and improves functional recovery after spinal cord injury through microglia polarization regulation.

Project description:Spinal cord injury (SCI) is a severe neurological disease; however, few drugs have been proved to treat SCI effectively. Neuroinflammation is the major pathogenesis of SCI secondary injury and considered to be the therapeutic target of SCI. Salidroside (Sal) has been reported to exert anti-inflammatory effects in airway, adipose and myocardial tissue; however, the role of Sal in SCI therapeutics has not been clarified. In this study, we showed that Sal could improve the functional recovery of spinal cord in rats as revealed by increased BBB locomotor rating scale, angle of incline, and decreased cavity of spinal cord injury and apoptosis of neurons in vivo. Immunofluorescence double staining of microglia marker and M1/M2 marker demonstrated that Sal could suppress M1 microglia polarization and activate M2 microglia polarization in vivo. To verify how Sal exerts its effects on microglia polarization and neuron protection, we performed the mechanism study in vitro in microglia cell line BV-2 and neuron cell line PC12. The results showed that Sal prevents apoptosis of PC12 cells in coculture with LPS-induced M1 BV-2 microglia, also the inflammatory secretion phenotype of M1 BV-2 microglia was suppressed by Sal, and further studies demonstrated that autophagic flux regulation through AMPK/mTOR pathway was involved in Sal regulated microglia polarization after SCI. Overall, our study illustrated that Sal could promote spinal cord injury functional recovery in rats, and the mechanism may relate to its microglia polarization modulation through AMPK-/mTOR-mediated autophagic flux stimulation.

| S-EPMC5783886 | biostudies-other

Upregulation of TRESK Channels Contributes to Motor and Sensory Recovery after Spinal Cord Injury.

Project description:TWIK (tandem-pore domain weak inward rectifying K+)-related spinal cord K+ channel (TRESK), a member of the two-pore domain K+ channel family, is abundantly expressed in dorsal root ganglion (DRG) neurons. It is well documented that TRESK expression is changed in several models of peripheral nerve injury, resulting in a shift in sensory neuron excitability. However, the role of TRESK in the model of spinal cord injury (SCI) has not been fully understood. This study investigates the role of TRESK in a thoracic spinal cord contusion model, and in transgenic mice overexpressed with the TRESK gene (TGTRESK). Immunostaining analysis showed that TRESK was expressed in the dorsal and ventral neurons of the spinal cord. The TRESK expression was increased by SCI in both dorsal and ventral neurons. TRESK mRNA expression was upregulated in the spinal cord and DRG isolated from the ninth thoracic (T9) spinal cord contusion rats. The expression was significantly upregulated in the spinal cord below the injury site at acute time points (6, 24, and 48 h) after SCI (p < 0.05). In addition, TRESK expression was markedly increased in DRGs below and adjacent to the injury site. TRESK was expressed in inflammatory cells. In addition, the number and fluorescence intensity of TRESK-positive neurons increased in the dorsal and ventral horns of the spinal cord after SCI. TGTRESK SCI mice showed faster paralysis recovery and higher mechanical threshold compared to wild-type (WT)-SCI mice. TGTRESK mice showed lower TNF-α concentrations in the blood than WT mice. In addition, IL-1β concentration and apoptotic signals in the caudal spinal cord and DRG were significantly decreased in TGTRESK SCI mice compared to WT-SCI mice (p < 0.05). These results indicate that TRESK upregulated following SCI contributes to the recovery of paralysis and mechanical pain threshold by suppressing the excitability of motor and sensory neurons and inflammatory and apoptotic processes.

| S-EPMC7731147 | biostudies-literature

Permanently Re-programmed Microglia in Spinal Cord Injury Contribute to Functional Recovery

Project description:Microglia are resident myeloid cells of the central nervous system (CNS). Recently, single-cell RNA sequencing (scRNAseq) has enabled description of a disease-associated subtype of microglia (DAM) with a role in neurodegeneration and demyelination. In this study we use scRNAseq to investigate the temporal dynamics of immune cells harvested from the epicenter of traumatic spinal cord injury (SCI). As a consequence of SCI, homeostatic microglia undergo permanent transcriptional re-programming into a subtype of microglia with striking similarities to previoysly reported DAM as well as a distinct microglial state found during development. Using a microglia depletion model we showed that DAM in SCI are derived from homeostatic microglia and strongly enhance recovery of hind limb locomotor function following injury.

2021-12-24 | GSE142849 | GEO

CSF1R Inhibition Reduces Microglia Proliferation, Promotes Tissue Preservation and Improves Motor Recovery After Spinal Cord Injury.

Project description:Spinal cord injury (SCI) induces a pronounced neuroinflammation driven by activation and proliferation of resident microglia as well as infiltrating peripheral monocyte-derived macrophages. Depending on the time post-lesion, positive and detrimental influences of microglia/macrophages on axonal regeneration had been reported after SCI, raising the issue whether their modulation may represent an attractive therapeutic strategy. Colony-stimulating factor 1 (CSF1) regulates microglia/macrophages proliferation, differentiation and survival thus, pharmacological treatments using CSF1 receptor (CSF1R) inhibitors had been used to ablate microglia. We analyzed the effect of chronic (10 weeks) food diet containing GW2580 (a CSF1R inhibitor) in mice that underwent lateral spinal cord hemisection (HS) at vertebral thoracic level 9. Treatment started 4 weeks prior to SCI and continued until 6 weeks post-lesion. We first demonstrate that GW2580 treatment did not modify microglial response in non-injured spinal cords. Conversely, a strong decrease in proliferating microglia was observed following SCI. Second, we showed that GW2580 treatment improved some parameters of motor recovery in injured animals through better paw placement. Using in and ex vivo magnetic resonance imaging (MRI), we then established that GW2580 treatment had no effect on lesion extension and volume. However, histological analyses revealed that GW2580-treated animals had reduced gliosis and microcavity formation following SCI. In conclusion, CSF1R blockade using GW2580 specifically inhibits SCI-induced microglia/macrophages proliferation, reduces gliosis and microcavity formations and improves fine motor recovery after incomplete SCI. Preventing microglial proliferation may offer therapeutic approach to limit neuroinflammation, promote tissue preservation and motor recovery following SCI.

| S-EPMC6198221 | biostudies-literature

Transplantation of M2-Deviated Microglia Promotes Recovery of Motor Function after Spinal Cord Injury in Mice.

Project description:Despite the poor prognosis of spinal cord injury (SCI), effective treatments are lacking. Diverse factors regulate SCI prognosis. In this regard, microglia play crucial roles depending on their phenotype. The M1 phenotype exacerbates neuroinflammation, whereas the M2 phenotype promotes tissue repair and provides anti-inflammatory effects. Therefore, we compared the effects of M2 and M1 microglia transplantation on SCI. First, we established a method for effective induction of M1 or M2 microglia by exposure to granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin (IL)-4, respectively, to be used for transplantation in a SCI mouse model. In the M2 microglia transplantation group, significant recovery of motor function was observed compared with the control and M1 groups. Elevated transcription of several neuroprotective molecules including mannose receptor C type 1 (Mrc1), arginase 1 (Arg1), and insulin-like growth factor 1 (Igf1) was observed. Moreover, intramuscular injection of FluoroRuby dye revealed recovery of retrograde axonal transport from the neuromuscular junction to upstream of the injured spinal cord only in the M2-transplanted group, although the number of migrated microglia were comparable in both M1 and M2 groups. In conclusion, our results indicated that M2 microglia obtained by IL-4 stimulation may be a promising candidate for cell transplantation therapy for SCI.

| S-EPMC6952178 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data