Lu Yuezhu, Guo Miao, Liu Yuming, Liu Haotian, Liao Mengyu, He Kai, Dong Xue, Wang Tian, Wang Heng, Zhong Yong, Yan Hua
Department of Ophthalmology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China.
Department of Ophthalmology, Tianjin Medical University General Hospital, International Joint Laboratory of Ocular Diseases (Ministry of Education), Tianjin Key Laboratory of Ocular Trauma, Laboratory of Molecular Ophthalmology, Tianjin Medical University, Tianjin, People's Republic of China.
Exp Eye Res. 2025 Sep;258:110505. doi: 10.1016/j.exer.2025.110505. Epub 2025 Jul 1.
Optic neuropathies significantly contribute to permanent vision loss, frequently characterized by the deterioration of retinal ganglion cells (RGCs) and axonal loss. Current therapeutic strategies remain insufficient. Induced pluripotent stem cell-derived extracellular vesicles (iPSC-EVs) have surfaced as a compelling substitute for stem cell therapies. Our study evaluates the neuroprotective effects of iPSC-EVs in a rat optic nerve crush (ONC) model. iPSC-EVs were isolated and characterized. The intravitreal (IVT) injections of iPSC-EVs or PBS were performed. RGCs survival was assessed at 7 and 14 days post-injury. Axonal regeneration was evaluated via anterograde labeling. Apoptosis of RGCs was detected using TUNEL assay. Retinal morphological changes and visual function recovery were assessed. Transcriptomic changes in the retina were analyzed by RNA sequencing to investigate potential underlying mechanisms. Additionally, Western blot was conducted to evaluate the expression levels of components in the phosphatidylinositol 3-kinases/protein kinase B (PI3K/AKT) pathway. The IVT injections of iPSC-EVs significantly improved RGCs survival and reduced neuronal apoptosis. Optical coherence tomography (OCT) revealed preservation of retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC) thickness, alongside reduced optic nerve atrophy. Functional recovery was evidenced by F-VEP and axonal regeneration was detected. Mechanistically, RNA sequencing and Western blot implicated the stimulation of the PI3K/AKT pathway. Our study shows that iPSC-EVs exert significant neuroprotective and regenerative effects in a rat ONC model, underscoring their promise as a novel treatment candidate for optic neuropathies.
视神经病变是导致永久性视力丧失的重要原因，其特征通常是视网膜神经节细胞（RGCs）退化和轴突损失。目前的治疗策略仍然不足。诱导多能干细胞衍生的细胞外囊泡（iPSC-EVs）已成为干细胞疗法的一种有吸引力的替代方案。我们的研究评估了iPSC-EVs在大鼠视神经挤压（ONC）模型中的神经保护作用。分离并鉴定了iPSC-EVs。进行了玻璃体内（IVT）注射iPSC-EVs或磷酸盐缓冲液（PBS）。在损伤后7天和14天评估RGCs的存活情况。通过顺行标记评估轴突再生。使用TUNEL检测法检测RGCs的凋亡。评估视网膜形态变化和视觉功能恢复情况。通过RNA测序分析视网膜中的转录组变化，以研究潜在的潜在机制。此外，进行蛋白质免疫印迹法以评估磷脂酰肌醇3-激酶/蛋白激酶B（PI3K/AKT）途径中各成分的表达水平。IVT注射iPSC-EVs显著提高了RGCs的存活率并减少了神经元凋亡。光学相干断层扫描（OCT）显示视网膜神经纤维层（RNFL）和神经节细胞复合体（GCC）厚度得以保留，同时视神经萎缩减轻。闪光视觉诱发电位（F-VEP）证明了功能恢复，并检测到轴突再生。从机制上讲，RNA测序和蛋白质免疫印迹法表明PI3K/AKT途径受到刺激。我们的研究表明，iPSC-EVs在大鼠ONC模型中发挥了显著的神经保护和再生作用，突出了它们作为视神经病变新型治疗候选物的前景。
