TIMP-3 Alleviates White Matter Injury After Subarachnoid Hemorrhage in Mice by Promoting Oligodendrocyte Precursor Cell Maturation

IF 3.6 4区 医学 Q3 CELL BIOLOGY
Peiwen Guo, Xufang Ru, Jiru Zhou, Mao Chen, Yanling Li, Mingxu Duan, Yuanshu Li, Wenyan Li, Yujie Chen, Shilun Zuo, Hua Feng
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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.

Graphical Abstract

Abstract Image

TIMP-3 通过促进少突胶质前体细胞成熟缓解小鼠蛛网膜下腔出血后的白质损伤
蛛网膜下腔出血(SAH)的死亡率和致残率都很高,继发性白质损伤是预后不良的重要原因。然而,脑毛细血管周细胞能否直接影响少突胶质细胞前体细胞(OPCs)的分化和成熟,进而影响白质损伤的修复,目前尚无定论。本研究旨在探讨组织金属蛋白酶抑制剂-3(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。小鼠在 SAH 后还接受了药物、TIMP-3 RNAi 或 TIMP-3 RNAi + TIMP-3 治疗。通过行为评分、酶联免疫吸附试验、透射电子显微镜、免疫荧光染色和细胞培养,确定了 TIMP-3 对 OPCs 分化和成熟的影响。我们发现,TIMP-3 主要由周细胞分泌,SAH 和 TIMP-3 RNAi 会导致 TIMP-3 含量显著下降,在 24 h 达到最低点,随后逐渐恢复。在体外,氧合血红蛋白处理后少突胶质细胞的髓鞘碱性蛋白含量通过 TIMP-3 的过表达而增加。这些数据表明,TIMP-3 可促进 OPCs 的分化和成熟,进而改善 SAH 后的神经功能预后。因此,TIMP-3 可能有利于白质损伤后的修复,并可能成为 SAH 的潜在治疗靶点。
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来源期刊
CiteScore
7.70
自引率
0.00%
发文量
137
审稿时长
4-8 weeks
期刊介绍: Cellular and Molecular Neurobiology publishes original research concerned with the analysis of neuronal and brain function at the cellular and subcellular levels. The journal offers timely, peer-reviewed articles that describe anatomic, genetic, physiologic, pharmacologic, and biochemical approaches to the study of neuronal function and the analysis of elementary mechanisms. Studies are presented on isolated mammalian tissues and intact animals, with investigations aimed at the molecular mechanisms or neuronal responses at the level of single cells. Cellular and Molecular Neurobiology also presents studies of the effects of neurons on other organ systems, such as analysis of the electrical or biochemical response to neurotransmitters or neurohormones on smooth muscle or gland cells.
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