Yao Yao, Bin Xin, Xu Yanxuan, Chen Shaowan, Chen Si, Yuan Xiang-Ling, Cao Yingjie, Ng Tsz Kin
Joint Shantou International Eye Center of Shantou University and The Chinese University of Hong Kong, Shantou, China.
Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China.
Cell Prolif. 2024 Dec;57(12):e13719. doi: 10.1111/cpr.13719. Epub 2024 Jul 18.
Traumatic optic neuropathy refers to optic nerve (ON) injury by trauma, including explosion and traffic accident. Retinal ganglion cell (RGC) death is the critical pathological cause of irreversible visual impairment and blindness in ON injury. We previously investigated the patterns of 11 modes of cell death in mouse retina post-ON injury. Here we aimed to identify additional signalling pathways regulating RGC survival in rodents post-ON injury. RNA sequencing analysis identified the upregulation of inflammation and cellular senescence-related genes in retina post-ON injury, which were confirmed by immunoblotting and immunofluorescence analyses. Increased expression of senescence-associated β-galactosidase (SA-βgal) in RGCs and activation of microglia were also found. Transforming growth factor-β receptor type II inhibitor (LY2109761) treatment suppressed p15 and p21 protein and SA-βgal expression and promoted RGC survival post-ON injury with decreasing the expression of cell death markers in retina. Consistently, senolytics (dasatinib and quercetin) treatments can promote RGC survival and alleviate the reduction of ganglion cell complex thickness and pattern electroretinography activity post-ON injury with reducing SA-βgal, p15, p21, microglial activation and cell death marker expression. In summary, this study revealed the activation of cellular senescence in rodent retina post-ON injury and contribute to RGC survival regulation. Targeting cellular senescence can promote RGC survival after ON injury, suggesting a potential treatment strategy for traumatic optic neuropathy.
外伤性视神经病变是指由外伤，包括爆炸和交通事故导致的视神经损伤。视网膜神经节细胞（RGC）死亡是视神经损伤中不可逆视力损害和失明的关键病理原因。我们之前研究了视神经损伤后小鼠视网膜11种细胞死亡模式。在此，我们旨在确定啮齿动物视神经损伤后调节RGC存活的其他信号通路。RNA测序分析确定了视神经损伤后视网膜中炎症和细胞衰老相关基因的上调，这通过免疫印迹和免疫荧光分析得到证实。还发现RGC中衰老相关β-半乳糖苷酶（SA-βgal）表达增加以及小胶质细胞活化。转化生长因子-βII型受体抑制剂（LY2109761）处理可抑制p15和p21蛋白以及SA-βgal表达，并通过降低视网膜中细胞死亡标志物的表达促进视神经损伤后RGC存活。同样，衰老细胞溶解剂（达沙替尼和槲皮素）处理可促进RGC存活，并减轻视神经损伤后神经节细胞复合体厚度和图形视网膜电图活性的降低，同时降低SA-βgal、p15、p21、小胶质细胞活化和细胞死亡标志物的表达。总之，本研究揭示了啮齿动物视神经损伤后视网膜细胞衰老的激活，并有助于RGC存活调节。靶向细胞衰老可促进视神经损伤后RGC存活，提示外伤性视神经病变的潜在治疗策略。
