中国神经再生研究(英文版) ›› 2025, Vol. 20 ›› Issue (2): 587-597.doi: 10.4103/NRR.NRR-D-23-01414

• 原著:视神经损伤修复保护与再生 • 上一篇    下一篇

诱导多能干细胞定向分化神经祖细胞来源小细胞外囊泡可减轻视神经损伤后视网膜神经节细胞变性

  

  • 出版日期:2025-02-15 发布日期:2024-06-18
  • 基金资助:
    国家自然科学基金项目(82271114);浙江省自然科学基金项目(LZ22H120001)

Small extracellular vesicles derived from human induced pluripotent stem cell-differentiated neural progenitor cells mitigate retinal ganglion cell degeneration in a mouse model of optic nerve injury

Tong Li1, #, Hui-Min Xing1, #, Hai-Dong Qian1, Qiao Gao1, Sheng-Lan Xu1, Hua Ma1, Zai-Long Chi1, 2, *   

  1. 1State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang Province, China; 2National Clinical Research Center for Ocular Diseases, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang Province, China
  • Online:2025-02-15 Published:2024-06-18
  • Contact: Zai-Long Chi, PhD, zailong.chi@eye.ac.cn.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, No. 82271114; the Natural Science Foundation of Zhejiang Province of China, No. LZ22H120001 (both to ZLC).

摘要:

许多研究发现,神经祖细胞移植可促进损伤神经元的存活。然而,移植后地整合率和高致癌风险高限制了其临床应用。小细胞外囊泡含有多种可参与神经元保护和再生的生物活性分子。既往研究已证实,干/祖细胞源性小细胞外囊泡可促进眼神经退行性疾病以及其他眼疾病中神经元存活和神经功能。此次实验将诱导多能干细胞定向分化神经祖细胞来源小细胞外囊泡通过玻璃体腔内注射的方式递送到视神经挤压损伤模型小鼠视网膜中。结果显示,小细胞外囊泡能够被视网膜内层神经节细胞以及多种胶质细胞摄取。诱导多能干细胞定向分化神经祖细胞来源小细胞外囊泡可减轻视神经挤压诱导的视网膜神经节细胞变性,并通过抑制小胶质细胞的过度活化来调节视网膜微环境。进一步分析发现,在视神经损伤后,诱导多能干细胞定向分化神经祖细胞来源小细胞外囊泡可通过向靶细胞递送一组神经祖细胞特异性神经保护和抗炎的微小RNA,促进视网膜神经节细胞存活,抑制胶质细胞激活。因此这种诱导多能干细胞定向分化神经祖细胞来源小细胞外囊泡是一种很有前途的治疗视神经损伤的无细胞治疗策略。

https://orcid.org/0009-0008-9597-6546 (Zai-Long Chi); https://orcid.org/0009-0002-4658-2109 (Tong Li)

关键词: 视神经病变, 视神经挤压, 神经祖细胞, 小细胞外囊泡, 外泌体, 微小RNA, 视网膜神经节细胞, 神经退行性变, 神经炎症, 神经保护

Abstract: Several studies have found that transplantation of neural progenitor cells (NPCs) promotes the survival of injured neurons. However, a poor integration rate and high risk of tumorigenicity after cell transplantation limits their clinical application. Small extracellular vesicles (sEVs) contain bioactive molecules for neuronal protection and regeneration. Previous studies have shown that stem/progenitor cell-derived sEVs can promote neuronal survival and recovery of neurological function in neurodegenerative eye diseases and other eye diseases. In this study, we intravitreally transplanted sEVs derived from human induced pluripotent stem cells (hiPSCs) and hiPSCs-differentiated NPCs (hiPSC-NPC) in a mouse model of optic nerve crush. Our results show that these intravitreally injected sEVs were ingested by retinal cells, especially those localized in the ganglion cell layer. Treatment with hiPSC-NPC-derived sEVs mitigated optic nerve crush-induced retinal ganglion cell degeneration, and regulated the retinal microenvironment by inhibiting excessive activation of microglia. Component analysis further revealed that hiPSC-NPC derived sEVs transported neuroprotective and anti-inflammatory miRNA cargos to target cells, which had protective effects on RGCs after optic nerve injury. These findings suggest that sEVs derived from hiPSC-NPC are a promising cell-free therapeutic strategy for optic neuropathy.

Key words: exosome, miRNA, neural progenitor cell, neurodegeneration, neuroinflammation, neuroprotection, optic nerve crush, optic neuropathy, retinal ganglion cell, small extracellular vesicles