Targeted homing of CCR2-overexpressing mesenchymal stromal cells to ischemic brain enhances post-stroke recovery partially through PRDX4-mediated blood-brain barrier preservation
Targeted homing of CCR2-overexpressing mesenchymal stromal cells to ischemic brain enhances post-stroke recovery partially through PRDX4-mediated blood-brain barrier preservation
复制标题
CCR2过表达间充质基质细胞靶向归巢至缺血性大脑可部分通过PRDX4介导的血脑屏障保护增强中风后恢复
DOI：
10.7150/thno.28029
复制
发表时间：
2018-01-01
期刊：
影响因子：
12.4
通讯作者：
Xiang, Andy Peng
中科院分区：
文献类型：
--
作者：
Huang, Yinong;Wang, Jiancheng;Xiang, Andy Peng
理论基础：间充质基质细胞(MSCs)是治疗急性缺血性中风(AIS)的一种新的治疗策略。然而，缺血区靶向迁移能力差、植入率低限制了其治疗效果。缺血性脑损伤表达特定的趋化因子谱，而培养的MSCs缺乏相应的受体。因此，我们假设某些趋化因子受体的过度表达可能有助于MSCs的归巢和提高治疗效果。方法：采用大鼠大脑中动脉闭塞(MCAO)模型，发现CCL2是同侧大脑半球表达最高的趋化因子之一。然后，我们将相应的受体CCR2基因转导到MSCs，并量化了MSCCCR2与MSCd番茄对照相比的细胞保留率。结果：MSCCCR2明显促进了向缺血区的迁移，改善了神经功能恢复。MSCCCR2处理组大鼠的脑水肿和血脑屏障(BBB)渗漏水平也比MSCd番茄组低得多。此外，这种血脑屏障保护减少了炎症渗透和活性氧物种(ROS)的产生。体外血脑屏障模型也证实了类似的结果。此外，全基因组RNA测序(RNA-seq)分析表明，过氧化还蛋白4(PRDX4)在MSCs中高表达，这主要与其对MCAO大鼠和缺氧缺糖(OGD)处理的内皮细胞的抗氧化作用有关。结论：CCR2在MSCs上的过表达增强了MSCs向缺血侧的靶向性迁移，改善了治疗效果，这归因于PRDX4介导的BBB保存。
Rationale: Mesenchymal stromal cells (MSCs) are emerging as a novel therapeutic strategy for the acute ischemic stroke (AIS). However, the poor targeted migration and low engraftment in ischemic lesions restrict their treatment efficacy. The ischemic brain lesions express a specific chemokine profile, while cultured MSCs lack the set of corresponding receptors. Thus, we hypothesize that overexpression of certain chemokine receptor might help in MSCs homing and improve therapeutic efficacy. Methods: Using the middle cerebral artery occlusion (MCAO) model of ischemic stroke, we identified that CCL2 is one of the most highly expressed chemokines in the ipsilateral hemisphere. Then, we genetically transduced the corresponding receptor, CCR2 to the MSCs and quantified the cell retention of MSCCCR2 compared to the MSCdtomato control. Results: MSCCCR2 exhibited significantly enhanced migration to the ischemic lesions and improved the neurological outcomes. Brain edema and blood-brain barrier (BBB) leakage levels were also found to be much lower in the MSCCCR2-treated rats than the MSCdtomato group. Moreover, this BBB protection led to reduced inflammation infiltration and reactive oxygen species (ROS) generation. Similar results were also confirmed using the in vitro BBB model. Furthermore, genome-wide RNA sequencing (RNA-seq) analysis revealed that peroxiredoxin4 (PRDX4) was highly expressed in MSCs, which mainly contributed to their antioxidant impacts on MCAO rats and oxygen-glucose deprivation (OGD)-treated endothelium. Conclusion: Taken together, this study suggests that overexpression of CCR2 on MSCs enhances their targeted migration to the ischemic hemisphere and improves the therapeutic outcomes, which is attributed to the PRDX4-mediated BBB preservation.