PDF(Pubmed)
Abstract：
Subarachnoid hemorrhage (SAH) is associated with high mortality and disability rates, and secondary white matter injury is an important cause of poor prognosis. However, whether brain capillary pericytes can directly affect the differentiation and maturation of oligodendrocyte precursor cells (OPCs) and subsequently affect white matter injury repair has still been revealed. This study was designed to investigate the effect of tissue inhibitor of metalloproteinase-3 (TIMP-3) for OPC differentiation and maturation. PDGFRβret/ret and wild-type C57B6J male mice were used to construct a mouse model of SAH via endovascular perforation in this study. Mice were also treated with vehicle, TIMP-3 RNAi or TIMP-3 RNAi + TIMP-3 after SAH. The effect of TIMP-3 on the differentiation and maturation of OPCs was determined using behavioral score, ELISA, transmission electron microscopy, immunofluorescence staining and cell culture. We found that TIMP-3 was secreted mainly by pericytes and that SAH and TIMP-3 RNAi caused a significant decrease in the TIMP-3 content, reaching a nadir at 24 h, followed by gradual recovery. In vitro, the myelin basic protein content of oligodendrocytes after oxyhemoglobin treatment was increased by TIMP-3 overexpression. The data indicates TIMP-3 could promote the differentiation and maturation of OPCs and subsequently improve neurological outcomes after SAH. Therefore, TIMP-3 could be beneficial for repair after white matter injury and could be a potential therapeutic target in SAH.
摘要：
蛛网膜下腔出血（SAH）与高死亡率和致残率相关，而继发性脑白质损伤是预后不良的重要原因。然而,脑毛细血管周细胞是否可以直接影响少突胶质前体细胞（OPCs）的分化和成熟，并随后影响白质损伤的修复。本研究旨在研究金属蛋白酶-3的组织抑制剂（TIMP-3）对OPC分化和成熟的影响。本研究使用PDGFRβret/ret和野生型C57B6J雄性小鼠通过血管内穿孔构建SAH小鼠模型。小鼠也用媒介物治疗，SAH后TIMP-3RNAi或TIMP-3RNAi+TIMP-3。TIMP-3对OPCs分化和成熟的影响使用行为评分，ELISA,透射电子显微镜,免疫荧光染色和细胞培养。我们发现TIMP-3主要由周细胞分泌，SAH和TIMP-3RNAi导致TIMP-3含量显着降低，在24小时达到最低点，随后逐步恢复。体外，TIMP-3过表达增加了氧合血红蛋白治疗后少突胶质细胞的髓鞘碱性蛋白含量.数据表明TIMP-3可以促进OPCs的分化和成熟,并随后改善SAH后的神经学结果。因此,TIMP-3可能有利于白质损伤后的修复，并且可能是SAH的潜在治疗靶标。
