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Induced neural stem cell-derived astrocytes modulate complement activation and mediate neuroprotection following closed head injury.

ABSTRACT: The complement system is a crucial component of immunity, and its activation has critical roles in neuroinflammatory response and cellular damage following closed head injury (CHI). We previously demonstrated that systemically injected induced neural stem cells (iNSCs) could modulate complement activation to ameliorate neuronal apoptosis in mouse CHI models. However, it remains unknown whether iNSC derivatives can regulate complement activation. In the present study, after CHI mouse serum treatment, we found dramatic decreases in the cellular viabilities of differentiated iNSCs. Interestingly, following CHI mouse serum treatment, the death of astrocytes derived from iNSCs which were pre-treated with CHI mouse serum was significantly decreased. Meanwhile, the deposition of C3 (C3d) and C5b-9 in these astrocytes was substantially reduced. Remarkably, we detected increased expression of complement receptor type 1-related protein y (Crry) in these astrocytes. Moreover, these astrocytes could reduce the numbers of apoptotic neurons via Crry expression post-CHI mouse serum treatment. Additionally, intracerebral-transplanted iNSCs, pre-treated with CHI mouse serum, significantly increased the levels of Crry expression in astrocytes to reduce the accumulation of C3d and C9 and the death of neurons in the brains of CHI mice. In summary, iNSCs receiving CHI mouse serum pre-treatment could enhance the expression of Crry in iNSC-derived astrocytes to modulate complement activation and mediate neuroprotection following CHI.

SUBMITTER: Gao M

PROVIDER: S-EPMC5833559 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Induced neural stem cell-derived astrocytes modulate complement activation and mediate neuroprotection following closed head injury.

Gao Mou M Dong Qin Q Lu Yingzhou Y Yao Hui H Zou Mingming M Yang Yang Y Zhu Jianwei J Yang Zhijun Z Xu Minhui M Xu Ruxiang R

Cell death & disease 20180124 2

The complement system is a crucial component of immunity, and its activation has critical roles in neuroinflammatory response and cellular damage following closed head injury (CHI). We previously demonstrated that systemically injected induced neural stem cells (iNSCs) could modulate complement activation to ameliorate neuronal apoptosis in mouse CHI models. However, it remains unknown whether iNSC derivatives can regulate complement activation. In the present study, after CHI mouse serum treatm ...[more]

PMID: 29367701

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Project description:BackgroundRecently, growing evidence has indicated an important role of the complement system, a crucial component of immunity, in mediating neuroinflammation and promoting neuronal apoptosis following closed head injury (CHI). We previously reported that transplanted induced neural stem cells (iNSCs) pre-treated with CHI mouse serum could enhance complement receptor type 1-related protein y (Crry) expression and ameliorate complement-mediated damage in mouse CHI models. However, the mechanism underlying the elevated levels of Crry expression remains elusive.MethodsCHI models were established using a standardized weight-drop device. We collected CHI mouse serum at 12 h post-trauma. RT-QPCR assay, western blot analysis, complement deposition assay, Akt inhibition assay, flow cytometry, cell transplantation, and functional assay were utilized to clarify the mechanism of Crry expression in iNSCs receiving CHI mouse serum treatment.ResultsWe observed dramatic increases in the levels of Crry expression and Akt activation in iNSCs receiving CHI mouse serum treatment. Remarkably, Akt inhibition led to the reduction of Crry expression in iNSCs. Intriguingly, the treatment of iNSC-derived neurons with recombinant complement receptor 2-conjugated Crry (CR2-Crry), which inhibits all complement pathways, substantially enhanced Crry expression and Akt activation in neurons after CHI mouse serum treatment. In subsequent in vitro experiments of pre-treatment of iNSCs with CR2-Crry, we observed significant increases in the levels of Crry expression and Akt activation in iNSCs and iNSC-derived astrocytes and neurons post-treatment with CHI mouse serum. Additionally, an in vivo study showed that intracerebral-transplanted iNSCs pre-treated with CR2-Crry markedly enhanced Crry expression in neurons and protected neurons from complement-dependent damage in the brains of CHI mice.ConclusionINSCs receiving CR2-Crry pre-treatment increased the levels of Crry expression in iNSCs and iNSC-derived astrocytes and neurons and attenuated complement-mediated injury following CHI.

Project description:Close-head concussive injury, as one of the most common forms of traumatic brain injury (TBI), has been shown to induce cognitive deficits that are long lasting. A concussive impact model was previously established in our lab that produces clinically relevant signs of concussion and induced acute pathological changes in rats. To evaluate the long-term effects of repeated concussions in this model, we utilized a comprehensive Morris water maze (MWM) paradigm for cognitive assessments at 1 and 6 months following repeated concussive impacts in rats. As such, adult Sprague-Dawley rats received either anesthesia (sham) or repeated concussive impacts (4 consecutive impacts at 1 h interval). At 1 month post-injury, results of the spatial learning task showed that the average latencies to locate the hidden "escape" platform were significantly longer in the injured rats over the last 2 days of the MWM testing compared to sham controls (p < 0.05). In the memory retention task, rats subjected to repeated concussive impacts also spent significantly less time in the platform zone searching for the missing platform during the probe trial (p < 0.05). On the working memory task, the injured rats showed a trend toward worse performance, but this failed to reach statistical significance compared to sham controls (p = 0.07). At 6 months post-injury, no differences were detected between the injured group and sham controls in either the spatial learning or probe trials. However, rats with repeated concussive impacts exhibited significantly worsened working memory performance compared to sham controls (p < 0.05). In addition, histopathological assessments for axonal neurodegeneration using silver stain showed that repeated concussive impacts induced significantly more axonal degeneration in the corpus callosum compared to sham controls (p < 0.05) at 1 month post-injury, whereas such difference was not observed at 6 months post-injury. Overall, the results show that repeated concussive impacts in our model produced significant cognitive deficits in both spatial learning abilities and in working memory abilities in a time-dependent fashion that may be indicative of progressive pathology and warrant further investigation.

Project description:Microglial activation is a pathological hallmark of traumatic brain injury (TBI). Following brain injury, activated microglia/macrophages adopt different phenotypes, generally categorized as M-1, or classically activated, and M-2, or alternatively activated. While the M-1, or pro-inflammatory phenotype is detrimental to recovery, M-2, or the anti-inflammatory phenotype, aids in brain repair. Recent findings also suggest the existence of mixed phenotype following brain injury, where activated microglia simultaneously express both M-1 and M-2 markers. The present study sought to determine microglial activation states at early time points (6-72 h) following single or repeated concussive injury in rats. Closed-head concussive injury was modeled in rats using projectile concussive impact injury, with either single or repeated impacts (4 impacts, 1 h apart). Brain samples were examined using immunohistochemical staining, inflammatory gene profiling and real-time polymerase chain reaction analyses to detect concussive injury induced changes in microglial activation and phenotype in cortex and hippocampal regions. Our findings demonstrate robust microglial activation following concussive brain injury. Moreover, we show that multiple concussions induced a unique rod-shaped microglial morphology that was also observed in other diffuse brain injury models. Histological studies revealed a predominance of MHC-II positive M-1 phenotype in the post-concussive microglial milieu following multiple impacts. Although there was simultaneous expression of M-1 and M-2 markers, gene expression results indicate a clear dominance in M-1 pro-inflammatory markers following both single and repeated concussions. While the increase in M-1 markers quickly resolved after a single concussion, they persisted following repeated concussions, indicating a pro-inflammatory environment induced by multiple concussions that may delay recovery and contribute to long-lasting consequences of concussion.

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Induced neural stem cell-derived astrocytes modulate complement activation and mediate neuroprotection following closed head injury.

Publications

Induced neural stem cell-derived astrocytes modulate complement activation and mediate neuroprotection following closed head injury.

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