CXCL12 Gene Therapy Ameliorates Ischemia-Induced White Matter Injury in Mouse Brain
CXCL12 Gene Therapy Ameliorates Ischemia-Induced White Matter Injury in Mouse Brain
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DOI：
10.5966/sctm.2015-0074
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发表时间：
2015-10-01
影响因子：
6
通讯作者：
Wang, Yongting
中科院分区：
文献类型：
--
作者：
Li, Yaning;Tang, Guanghui;Wang, Yongting
髓鞘再生是缺血性脑卒中后脑白质损伤的重要修复过程。由于少突胶质细胞祖细胞（OPCs）在脱髓鞘部位的募集不足或OPCs向少突胶质细胞的分化效率低下，导致其失败。我们研究了CXCL12基因治疗是否促进成年小鼠大脑中动脉闭塞后的再髓鞘形成。结果显示，缺血后1周CXCL12基因治疗可保护局灶周围髓鞘完整性，增加室下区血小板衍生生长因子受体α (PDGFR α)阳性和PDGFR α /溴脱氧尿嘧啶双阳性OPCs的数量，并进一步增强其向缺血性病变区域的迁移。与CXCL12受体CXCR4拮抗剂AMD3100联合使用，消除了CXCL12对髓鞘完整性的有益作用，并对OPC的增殖和迁移产生负面影响。缺血5周后，CXCR4出现在PDGFR α -和/或神经元/胶质2型（NG2）阳性的OPCs上，而未出现在髓鞘碱性蛋白阳性的成熟髓鞘上，CXCR7仅在缺血小鼠脑的成熟髓鞘上表达。我们的数据表明，CXCL12基因治疗可以有效地保护脑白质，促进脑白质在缺血性损伤后的修复。缺血后1周的治疗是有效的，这表明这种策略比目前可用的治疗方法有更长的治疗时间窗口。干细胞转化医学2015；4:1122 - 1130
Remyelination is an important repair process after ischemic stroke-induced white matter injury. It often fails because of the insufficient recruitment of oligodendrocyte progenitor cells (OPCs) to the demyelinated site or the inefficient differentiation of OPCs to oligodendrocytes. We investigated whether CXCL12 gene therapy promoted remyelination after middle cerebral artery occlusion in adult mice. The results showed that CXCL12 gene therapy at 1 week after ischemia could protect myelin sheath integrity in the perifocal region, increase the number of platelet-derived growth factor receptor-alpha (PDGFR alpha)-positive and PDGFR alpha/bromodeoxyuridine-double positive OPCs in the subventricular zone, and further enhance their migration to the ischemic lesion area. Coadministration of AMD3100, the antagonist for CXCL12 receptor CXCR4, eliminated the beneficial effect of CXCL12 on myelin sheath integrity and negatively influenced OPC proliferation and migration. At 5 weeks after ischemia, CXCR4 was found on the PDGFR alpha- and/or neuron/glia type 2 (NG2)-positive OPCs but not on the myelin basic protein-positive mature myelin sheaths, and CXCR7 was only expressed on the mature myelin sheath in the ischemic mouse brain. Our data indicated that CXCL12 gene therapy effectively protected white matter and promoted its repair after ischemic injury. The treatment at 1 week after ischemia is effective, suggesting that this strategy has a longer therapeutic time window than the treatments currently available. STEM CELLS TRANSLATIONAL MEDICINE 2015;4:1122-1130