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Overexpression of the transcription factors OCT4 and KLF4 improves motor function after spinal cord injury.

ABSTRACT: INTRODUCTION:Astrogliosis and glial scar formation following spinal cord injury (SCI) are viewed as major obstacles that hinder axonal regeneration and functional recovery. Regulating the glial scar and axonal regeneration in the lesion site is important for treating SCI. AIMS:Considering the important role of astrocyte in glial scar formation and subsequent axonal regeneration, we intended to investigate the effect of the transcription factors OCT4 and KLF4 on astrocyte and the underlying mechanism after spinal cord contusion injury in transgenic mice. RESULTS:Western blotting, q-PCR, immunofluorescence, and functional evaluation suggested that glial fibrillary acidic protein (GFAP) expression decreased in the lesion area, the porosity of the scar increased, and remyelination enhanced. Mice overexpressing the transcription factors OCT4 and KLF4 had higher Basso Mouse Scale scores than did the control mice. Moreover, using immunofluorescence and Western blotting, we discovered that some astrocytes expressed nestin and sox2 protein, suggesting that these astrocytes were reprogrammed into neural stem cell-like cells. Furthermore, a cell scratch assay showed that the migration ability of the astrocytes was significantly inhibited in the presence of the transcription factors OCT4 and KLF4. In addition, we demonstrated that the Hippo/Yap pathway was activated after these two transcription factors overexpressed in astrocytes. CONCLUSIONS:In summary, these results suggest that overexpression of the transcription factors OCT4 and KLF4 could induce astrocyte reprogramming, which subsequently improves remyelination and functional recovery after SCI.

SUBMITTER: Huang X

PROVIDER: S-EPMC7415207 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Overexpression of the transcription factors OCT4 and KLF4 improves motor function after spinal cord injury.

Huang Xianpeng X Wang Chenggui C Zhou Xiaopeng X Wang Jingkai J Xia Kaishun K Yang Biao B Gong Zhe Z Ying Liwei L Yu Chao C Shi Kesi K Shu Jiawei J Cheng Feng F Han Bin B Liang Chengzhen C Li Fangcai F Chen Qixin Q

CNS neuroscience & therapeutics 20200525 9

<h4>Introduction</h4>Astrogliosis and glial scar formation following spinal cord injury (SCI) are viewed as major obstacles that hinder axonal regeneration and functional recovery. Regulating the glial scar and axonal regeneration in the lesion site is important for treating SCI.<h4>Aims</h4>Considering the important role of astrocyte in glial scar formation and subsequent axonal regeneration, we intended to investigate the effect of the transcription factors OCT4 and KLF4 on astrocyte and the u ...[more]

PMID: 32449258

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Project description:Spinal cord injury is a challenge in orthopedics because it causes irreversible damage to the central nervous system. Therefore, early treatment to prevent lesion expansion is crucial for the management of patients with spinal cord injury. Bexarotene, a type of retinoid, exerts therapeutic effects on patients with cutaneous T-cell lymphoma and Parkinson's disease. Bexarotene has been proven to promote autophagy, but it has not been used in the treatment of spinal cord injury. To investigate the effects of bexarotene on spinal cord injury, we established a mouse model of T11-T12 spinal cord contusion and performed daily intraperitoneal injection of bexarotene for 5 consecutive days. We found that bexarotene effectively reduced the deposition of collagen and the number of pathological neurons in the injured spinal cord, increased the number of synapses of nerve cells, reduced oxidative stress, inhibited pyroptosis, promoted the recovery of motor function, and reduced death. Inhibition of autophagy with 3-methyladenine reversed the effects of bexarotene on spinal cord injury. Bexarotene enhanced the nuclear translocation of transcription factor E3, which further activated AMP-activated protein kinase-S-phase kinase-associated protein 2-coactivator-associated arginine methyltransferase 1 and AMP-activated protein kinase-mammalian target of rapamycin signaling pathways. Intravenous injection of transcription factor E3 shRNA or intraperitoneal injection of compound C, an AMP-activated protein kinase blocker, inhibited the effects of bexarotene. These findings suggest that bexarotene regulates nuclear translocation of transcription factor E3 through the AMP-activated protein kinase-S-phase kinase-associated protein 2-coactivator-associated arginine methyltransferase 1 and AMP-activated protein kinase-mammalian target of rapamycin signal pathways, promotes autophagy, decreases reactive oxygen species level, inhibits pyroptosis, and improves motor function after spinal cord injury.

Project description:BackgroundThe anti-inflammatory cytokine interleukin-10 (IL-10) has been explored previously as a treatment method for spinal cord injury (SCI) due to its ability to attenuate pro-inflammatory cytokines and reduce apoptosis. Primary limitations when using systemic injections of IL-10 are that it is rapidly cleared from the injury site and that it does not cross the blood-spinal cord barrier.ObjectiveHere, mineral-coated microparticles (MCMs) were used to obtain a local sustained delivery of IL-10 directly into the injury site after SCI.MethodsFemale Sprague-Dawley rats were contused at T10 and treated with either an intraperitoneal injection of IL-10, an intramedullary injection of IL-10, or MCMs bound with IL-10 (MCMs+IL-10). After treatment, cytokine levels were measured in the spinal cord, functional testing and electrophysiology were performed, axon tracers were injected into the brainstem and motor cortex, macrophage levels were counted using flow cytometry and immunohistochemistry, and lesion size was measured.ResultsWhen treated with MCMs+IL-10, IL-10 was significantly elevated in the injury site and inflammatory cytokines were significantly suppressed, prompting significantly less cells expressing antigens characteristic of inflammatory macrophages and significantly more cells expressing antigens characteristic of earlier stage anti-inflammatory macrophages. Significantly more axons were preserved within the rubrospinal and reticulospinal tracts through the injury site when treated with MCMs+IL-10; however, there was no significant difference in corticospinal tract axons preserved, regardless of treatment group. The rats treated with MCMs+IL-10 were the only group with a significantly higher functional score compared to injured controls 28 days post-contusion.ConclusionThese data demonstrate that MCMs can effectively deliver biologically active IL-10 for an extended period of time altering macrophage phenotype and aiding in functional recovery after SCI.

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Overexpression of the transcription factors OCT4 and KLF4 improves motor function after spinal cord injury.

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Overexpression of the transcription factors OCT4 and KLF4 improves motor function after spinal cord injury.

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