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Neural stem cell transplantation inhibits glial cell proliferation and P2X receptor-mediated neuropathic pain in spinal cord injury rats.

ABSTRACT: P2X4 and P2X7 receptors play an important role in neuropathic pain after spinal cord injury. Regulation of P2X4 and P2X7 receptors can obviously reduce pain hypersensitivity after injury. To investigate the role of neural stem cell transplantation on P2X receptor-mediated neuropathic pain and explore related mechanisms, a rat model of spinal cord injury was prepared using the free-falling heavy body method with spinal cord segment 10 as the center. Neural stem cells were injected into the injured spinal cord segment using a micro-syringe. Expression levels of P2X4 and P2X7 receptors, neurofilament protein, and glial fibrillary acidic protein were determined by immunohistochemistry and western blot assay. In addition, sensory function was quantitatively assessed by current perception threshold. The Basso-Beattie-Bresnahan locomotor rating scale was used to assess neuropathological pain. The results showed that 4 weeks after neural stem cell transplantation, expression of neurofilament protein in the injured segment was markedly increased, while expression of glial fibrillary acidic protein and P2X4 and P2X7 receptors was decreased. At this time point, motor and sensory functions of rats were obviously improved, and neuropathic pain was alleviated. These findings demonstrated that neural stem cell transplantation reduced overexpression of P2X4 and P2X7 receptors, activated locomotor and sensory function reconstruction, and played an important role in neuropathic pain regulation after spinal cord injury. Therefore, neural stem cell transplantation is one potential option for relieving neuropathic pain mediated by P2X receptors.

SUBMITTER: Du XJ

PROVIDER: S-EPMC6375052 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Neural stem cell transplantation inhibits glial cell proliferation and P2X receptor-mediated neuropathic pain in spinal cord injury rats.

Du Xiao-Jing XJ Chen Yue-Xia YX Zheng Zun-Cheng ZC Wang Nan N Wang Xiao-Yu XY Kong Fan-E FE

Neural regeneration research 20190501 5

P2X4 and P2X7 receptors play an important role in neuropathic pain after spinal cord injury. Regulation of P2X4 and P2X7 receptors can obviously reduce pain hypersensitivity after injury. To investigate the role of neural stem cell transplantation on P2X receptor-mediated neuropathic pain and explore related mechanisms, a rat model of spinal cord injury was prepared using the free-falling heavy body method with spinal cord segment 10 as the center. Neural stem cells were injected into the injure ...[more]

PMID: 30688274

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Project description:BackgroundNeuropathic pain (NP), which results from injury or lesion of the somatosensory nervous system, is intimately associated with glial cells. The roles of microglia and astrocytes in NP have been broadly described, while studies on oligodendrocytes have largely focused on axonal myelination. The mechanisms of oligodendrocytes and their interactions with other glial cells in NP development remain uncertain.MethodsTo explore the function of the interaction of the three glial cells and their interactions on myelin development in NP, we evaluated changes in NP and myelin morphology after a chronic constriction injury (CCI) model in mice, and used single-cell sequencing to reveal the subpopulations characteristics of oligodendrocytes, microglia, and astrocytes in the spinal cord tissues, as well as their relationship with myelin lesions; the proliferation and differentiation trajectories of oligodendrocyte subpopulations were also revealed using pseudotime cell trajectory and RNA velocity analysis. In addition, we identified chemokine ligand-receptor pairs between glial cells by cellular communication and verified them using immunofluorescence.ResultsOur study showed that NP peaked on day 7 after CCI in mice, a time at which myelin lesions were present in both the spinal cord and sciatic nerve. Oligodendrocytes, microglia, and astrocytes subpopulations in spinal cord tissue were heterogeneous after CCI and all were involved in suppressing the process of immune defense and myelin production. In addition, the differentiation trajectory of oligodendrocytes involved a unidirectional lattice process of OPC-1-Oligo-9, which was arrested at the Oligo-2 stage under the influence of microglia and astrocytes. And the CADM1-CADM1, NRP1-VEGFA interactions between glial cells are enhanced after CCI and they had a key role in myelin lesions and demyelination.ConclusionsOur study reveals the close relationship between the differentiation block of oligodendrocytes after CCI and their interaction with microglia and astrocytes-mediated myelin lesions and NP. CADM1/CADM1 and NRP-1/VEGFA may serve as potential therapeutic targets for use in the treatment of NP.

Project description:Neuropathic pain, a debilitating pain condition, is a common consequence of damage to the nervous system. Optimal treatment of neuropathic pain is a major clinical challenge because the underlying mechanisms remain unclear and currently available treatments are frequently ineffective. Emerging lines of evidence indicate that peripheral nerve injury converts resting spinal cord glia into reactive cells that are required for the development and maintenance of neuropathic pain. However, the mechanisms underlying reactive astrogliosis after nerve injury are largely unknown. In the present study, we investigated cell proliferation, a critical process in reactive astrogliosis, and determined the temporally restricted proliferation of dorsal horn astrocytes in rats with spinal nerve injury, a well-known model of neuropathic pain. We found that nerve injury-induced astrocyte proliferation requires the Janus kinase-signal transducers and activators of transcription 3 signalling pathway. Nerve injury induced a marked signal transducers and activators of transcription 3 nuclear translocation, a primary index of signal transducers and activators of transcription 3 activation, in dorsal horn astrocytes. Intrathecally administering inhibitors of Janus kinase-signal transducers and activators of transcription 3 signalling to rats with nerve injury reduced the number of proliferating dorsal horn astrocytes and produced a recovery from established tactile allodynia, a cardinal symptom of neuropathic pain that is characterized by pain hypersensitivity evoked by innocuous stimuli. Moreover, recovery from tactile allodynia was also produced by direct suppression of dividing astrocytes by intrathecal administration of the cell cycle inhibitor flavopiridol to nerve-injured rats. Together, these results imply that the Janus kinase-signal transducers and activators of transcription 3 signalling pathway are critical transducers of astrocyte proliferation and maintenance of tactile allodynia and may be a therapeutic target for neuropathic pain.

Project description:BackgroundThe participation of spinal P2X receptors in neuropathic pain is well recognized. However, the role of P2Y receptors has been less studied. The purpose of this study was to investigate the contribution of spinal P2Y6,11 receptors following peripheral nerve damage induced by spinal nerve ligation. In addition, we determined the expression of P2Y6,11 receptors in the dorsal spinal cord in presence of the selective P2Y6,11 receptors antagonists. Furthermore, we evaluated the participation of spinal microglia and astrocytes in the pronociceptive role of P2Y6,11 receptors.ResultsSpinal administration of the selective P2Y6 (MRS2578, 10-100 ?M) and P2Y11 (NF340, 0.3-30 ?M) receptor antagonists reduced tactile allodynia in spinal nerve ligated rats. Nerve injury increased the expression of P2Y6,11 receptors at 7, 14 and 21 days after injury. Furthermore, intrathecal administration of MRS2578 (100 ?M/day) and NF340 (30 ?M/day) for 3 days significantly reduced spinal nerve injury-induced increase in P2Y6,11 receptors expression, respectively. Spinal treatment (on day 14 after injury) with minocycline (100 ?g/day) or fluorocitrate (1 nmol/day) for 7 days reduced tactile allodynia and spinal nerve injury-induced up-regulation in Iba-1 and GFAP, respectively. In addition, minocycline reduced nerve injury-induced up-regulation in P2Y6,11 receptors whereas that fluorocitrate diminished P2Y11, but not P2Y6, receptors up-regulation. Intrathecal treatment (on day 21 after injury) with the selective P2Y6 (PSB0474, 3-30 ?M) and P2Y11 (NF546, 1-10 ?M) receptor agonists produced remarkable tactile allodynia in nerve ligated rats previously treated with minocycline or fluorocitrate for 7 days.ConclusionsOur data suggest that spinal P2Y6 is present in spinal microglia while P2Y11 receptors are present in both spinal microglia and astrocytes, and both receptors are up-regulated in rats subjected to spinal nerve injury. In addition, our data suggest that the spinal P2Y6 and P2Y11 receptors participate in the maintenance of neuropathic pain.

Project description:Objective: Chronic pain is a major problem in patients with spinal cord injury (SCI). According to different studies, approximately 70% of patients with SCI experience persistent pain. Although previous gene expression profiling studies have been conducted in animal models, gene expression profiling study in human whole blood has not been reported yet. The objective of this study was to define the gene expression profile of neuropathic pain in spinal cord injured patients. Materials and Methods: We performed gene expression analysis including 20.000 genes using Affymetrix GeneChip® Primeview™ Human Gene Expression Arrays. For confirmation of expression levels of selected genes, we performed real time polymerase chain reaction. We gathered samples from periferic blood mononuclear cells. Data of twelve patients with intractable neuropathic pain was compared with thirteen patients who don’t have pain. All patients have complete injuries with a level of injury above T5. Results: A total of 16 differentially expressed genes including 9 up-regulated and 7 down-regulated were obtained with a cut-off degree at 4 fold change. EIF1AY, RPS4Y1, DDX3Y, RPL31, ETS1, KLF3, JUN, CYorf15B, and ERAP2 were in up-regulated and HLA-C, XIST, C4BPA, FAM118A, ZNF506, OVOS2, and C1D were in down-regulated group. KEGG pathway database showed that 14.6% of genes were enriched in the nodes of immune system. Real time polymerase chain reaction analyses did not increase to statistically significant levels for confirmation of gene expression analyze results. Conclusions: Considering these data, findings of this first gene expression study in humans with SCI might provide valuable information for future targets for understanding neuropathic pain pathogenesis. The results of gene expression analyses were not confirmed by real time polymerase chain reaction. Studies with larger sample size are needed for confirmation. This is a cross-sectional study with a control group. Patients were divided into two groups according to intractable neuropathic pain existence.There were 12 patients in group A (Patients with pain) and 13 patients in control group.

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Neural stem cell transplantation inhibits glial cell proliferation and P2X receptor-mediated neuropathic pain in spinal cord injury rats.

Publications

Neural stem cell transplantation inhibits glial cell proliferation and P2X receptor-mediated neuropathic pain in spinal cord injury rats.

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