期刊
THERANOSTICS
卷 8, 期 21, 页码 5929-5944出版社
IVYSPRING INT PUBL
DOI: 10.7150/thno.28029
关键词
Mesenchymal stromal cells; CCL2/CCR2; blood brain barrier; endothelium; PRDX4
资金
- National Key Research and Development Program of China, Stem cell and Translational Research [2018YFA0107203, 2017YFA0103403]
- Strategic Priority Research Program of the Chinese Academy of Sciences [XDA16020701]
- National Natural Science Foundation of China [81425016, 81730005, 31771616, 81671178]
- Key Scientific and Technological Projects of Guangdong Province [2014B020226002, 2015B020228001, 2015B020229001, 2016B030230001, 2017B020231001]
- Natural Science Foundation of Guangdong Province [2014A030310049, S2013030013305, 2017A030310237, 2017A030311013]
- Key Scientific and Technological Program of Guangzhou City [201803040011, 201704020223, 201604020132]
- Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme (GDUPS)
- China Postdoctoral Science Foundation [2016M602583, 2017T100657]
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.
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