Targeted homing of CCR2-overexpressing mesenchymal stromal cells to ischemic brain enhances post-stroke recovery partially through PRDX4-mediated blood-brain barrier preservation

作者：Yinong Huang, Jiancheng Wang, Jianye Cai, Yuan Qiu, Haiqing Zheng, Xiaofan Lai, Xin Sui, Yi Wang, Qiying Lu, Yanan Zhang, Meng Yuan, Jin Gong, Wei Cai, Xin Liu, Yilong Shan, Zhezhi Deng, Yue Shi, Yaqing Shu, Lei Zhang, Wei Qiu, Lisheng Peng, Jie Ren, Zhengqi Lu, Andy Peng Xiang · 发表于：Theranostics · 年份：2018 · DOI：10.7150/thno.28029 · 被引用次数：100 · 研究领域：Neuroinflammation and Neurodegeneration Mechanisms、Mesenchymal stem cell research、Neurological Disease Mechanisms and Treatments

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 MSC CCR2 compared to the MSC dtomato control. Results: MSC CCR2 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 MSC CCR2 -treated rats than the MSC dtomato 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 oxyge...