Cellular and Molecular Gradients in the Ventral Horns With Increasing Distance From the Injury Site After Spinal Cord Contusion

Kabdesh, Ilyas; Mukhamedshina, Yana; Arkhipova, Svetlana S.; Sabirov, Davran; Kuznecov, Maxim S.; Vyshtakalyuk, A. B.; Rizvanov, Albert A.; James, Victoria; Chelyshev, Yu. A.

doi:10.3389/fncel.2022.817752

Cited by 5 publications

(7 citation statements)

References 50 publications

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“…Paradoxically, astrocyte perisynaptic processes marker GLT-1 was only increased in expression in 2-3 segments adjacent to the epicenter, which was measured both at 7 and 30 dpi. At 30 dpi, the square occupied by synaptophysin spots on the MNs perikarya and dendritic spines decreased [123]. These data indicate that, at least in the caudal direction, the synaptic loss is observed both near and at the already mentioned above greater distance from the area of damage.…”

Section: Perilesional Zone -Adjacent Segmentssupporting

confidence: 56%

“…Astrocytes near the injury site are actively involved in the remodeling of the extracellular matrix and synthesis of CSPGs that specifically inhibit axonal growth. Analysis of the astrocyte marker GFAP showed increased expression in adjacent segments, spreading more distally from the injury site [122,123]. These data indicate that the inhibitory effect of these molecules on axon growth manifests not only in the well-known immediate vicinity of the injury epicenter, but also at a distance from it.…”

Section: Perilesional Zone -Adjacent Segmentsmentioning

confidence: 69%

“…Of note, there is a gradient of NG2/CSPG4 expression, with the highest level focused close to the injury site. A decrease in NG2/CSPG4 correlates with a decrease in the number of NG2 cells more distally [123]. After SCI, in segments 1-2 adjacent to the epicenter, the GFAP-positive processes expression of NG2/CSPG4 depends on the distance of these processes from the perikaryon of neurons.…”

Section: Perilesional Zone -Adjacent Segmentsmentioning

confidence: 91%

“…The perilesion perimeter in the ventral horns (VH) was characterized by shifts in the expression of molecules that control neuroplasticity and axonal growth [122]. After severe thoracic SCI in a rat model, in the VH of 1-2 adjacent caudal segments a significant decrease was shown in the number of descending serotonergic axons that control basic locomotion [123].…”

Section: Perilesional Zone -Adjacent Segmentsmentioning

confidence: 99%

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More Attention on Segments Remote from the Primary Spinal Cord Lesion Site

Chelyshev¹

2022

Front. Biosci. (Landmark Ed)

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Recent findings from multimodal imaging studies point to macrostructural pathological changes in areas significantly distant from the epicenter of spinal cord injury, both in the spinal cord and in the brain. Studies are being performed to determine cellular and molecular mechanisms of these shifts, which are currently poorly understood. Research has demonstrated that the pathological process in the remote area is multifaceted. This process involves astrocytes and microglia, which contribute to the degeneration of nerve fibers passing from and through the immediate impact area, as well as participate in reciprocal activation. As a result, there is accompanying synaptic loss in areas remote to the spinal cord injury location. Reactive astrocytes produce chondroitin sulfate proteoglycans that inhibit axon growth and damage cells. However, neuronal death in the remote area remains controversial. The area of primary injury is the source of numerous neurotoxic molecules that release into the cerebrospinal fluid. It is assumed that these molecules, primarily matrix metalloproteinases, disrupt the blood-spinal cord barrier, which leads to tissue infiltration by macrophage precursors in the remote area. Activated macrophages secrete pro-inflammatory cytokines and matrix metalloproteinases, which, in turn, induce astrocytes and microglia towards a pro-inflammatory phenotype. In addition, reactive microglia, together with astrocytes, secrete numerous pro-inflammatory and neurotoxic molecules that activate inflammatory signaling pathways, consequently exacerbating synaptic depletion and neurological deterioration. It appears likely that the interplay between chronic inflammation and neurodegeneration is a pivotal characteristic of the pathological process in the spinal cord areas distant from the epicenter of the lesion. Pathological changes in the distant areas should be the object of research as potential therapeutic targets.

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Section: Perilesional Zone -Adjacent Segmentssupporting

confidence: 56%

Section: Perilesional Zone -Adjacent Segmentsmentioning

confidence: 69%

Section: Perilesional Zone -Adjacent Segmentsmentioning

confidence: 91%

Section: Perilesional Zone -Adjacent Segmentsmentioning

confidence: 99%

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More Attention on Segments Remote from the Primary Spinal Cord Lesion Site

Chelyshev¹

2022

Front. Biosci. (Landmark Ed)

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“…10E, F). A recent study also confirmed ◂ the diffusion of the wound response to adjacent and remote areas [123]. Conventional wisdom holds that secondary injury following SCI can be temporally divided into acute, sub-acute, and chronic phases [1,3,10,13,20,65].…”

Section: The Scar Boundary Is Interpreted By Stmentioning

confidence: 76%

Spatiotemporal Dynamics of the Molecular Expression Pattern and Intercellular Interactions in the Glial Scar Response to Spinal Cord Injury

Gong

Han

et al. 2022

Neurosci. Bull.

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Nerve regeneration in adult mammalian spinal cord is poor because of the lack of intrinsic regeneration of neurons and extrinsic factors – the glial scar is triggered by injury and inhibits or promotes regeneration. Recent technological advances in spatial transcriptomics (ST) provide a unique opportunity to decipher most genes systematically throughout scar formation, which remains poorly understood. Here, we first constructed the tissue-wide gene expression patterns of mouse spinal cords over the course of scar formation using ST after spinal cord injury from 32 samples. Locally, we profiled gene expression gradients from the leading edge to the core of the scar areas to further understand the scar microenvironment, such as neurotransmitter disorders, activation of the pro-inflammatory response, neurotoxic saturated lipids, angiogenesis, obstructed axon extension, and extracellular structure re-organization. In addition, we described 21 cell transcriptional states during scar formation and delineated the origins, functional diversity, and possible trajectories of subpopulations of fibroblasts, glia, and immune cells. Specifically, we found some regulators in special cell types, such as Thbs1 and Col1a2 in macrophages, CD36 and Postn in fibroblasts, Plxnb2 and Nxpe3 in microglia, Clu in astrocytes, and CD74 in oligodendrocytes. Furthermore, salvianolic acid B, a blood–brain barrier permeation and CD36 inhibitor, was administered after surgery and found to remedy fibrosis. Subsequently, we described the extent of the scar boundary and profiled the bidirectional ligand-receptor interactions at the neighboring cluster boundary, contributing to maintain scar architecture during gliosis and fibrosis, and found that GPR37L1_PSAP, and GPR37_PSAP were the most significant gene-pairs among microglia, fibroblasts, and astrocytes. Last, we quantified the fraction of scar-resident cells and proposed four possible phases of scar formation: macrophage infiltration, proliferation and differentiation of scar-resident cells, scar emergence, and scar stationary. Together, these profiles delineated the spatial heterogeneity of the scar, confirmed the previous concepts about scar architecture, provided some new clues for scar formation, and served as a valuable resource for the treatment of central nervous system injury.

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Increased astrocytic GLT-1 expression in tripartite synapses is associated with SCI-induced hyperreflexia

Benson,

King,

Kauer

et al. 2023

Journal of Neurophysiology

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Spasticity is a chronic neurological complication associated with spinal cord injury (SCI), characterized by increased muscle tone and stiffness. A physiological sign of spasticity is hyperreflexia, evident by the loss of evoked rate-dependent depression (RDD) in the monosynaptic spinal circuit, i.e., H-reflex. Although previous work has shown that SCI-induced astrogliosis contributes to hyperexcitability disorders, including neuropathic pain and spasticity, it is unclear how reactive astrocytes can modulate synaptic transmission within the injured spinal cord. To study astrocytes' role in post-SCI hyperreflexia, we examined GLT-1 and PSD-95 proteins in astrocytes and neurons, respectively, within the ventral horn (lamina IX). The close juxtaposition of GLT-1 and PSD-95 markers is a molecular correlate of tripartite synapses and is thought to be a key element in astrocyte-induced plasticity of neuronal synapses. Our study compared animals with and without SCI-induced hyperreflexia and spasticity, and investigated potential synaptic abnormalities associated with astrocyte involvement. As expected, four weeks after SCI, we observed a loss in evoked H-reflex RDD in hindlimb EMG recordings, i.e., hyperreflexia, in contrast to uninjured Sham. Importantly, our main findings show a significant increase in the presence of GLT-1 - PSD-95 tripartite synapses in the ventral spinal cord motor regions of animals exhibiting SCI-induced hyperreflexia. Taken together, our study provides clear evidence supporting the involvement of astrocyte-neuron synaptic complexes in the in the plasticity-driven progression of chronic spasticity.

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Cellular and Molecular Gradients in the Ventral Horns With Increasing Distance From the Injury Site After Spinal Cord Contusion

Cited by 5 publications

References 50 publications

More Attention on Segments Remote from the Primary Spinal Cord Lesion Site

More Attention on Segments Remote from the Primary Spinal Cord Lesion Site

Spatiotemporal Dynamics of the Molecular Expression Pattern and Intercellular Interactions in the Glial Scar Response to Spinal Cord Injury

Increased astrocytic GLT-1 expression in tripartite synapses is associated with SCI-induced hyperreflexia

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