Dynamic Transcriptomic Remodeling in Grafted Human Neural Progenitor Cells Uncovers Mechanisms for Vision Preservation in Retinitis Pigmentosa

Human neural progenitor cells (hNPCs) show promise in slowing retinal degeneration and are currently being tested in clinical trials for retinitis pigmentosa (RP). However, the long-term fate of grafted hNPCs and their interaction with host retinal cells remains unclear. Here, we used single-cell transcriptomics to investigate temporal gene expression changes in grafted hNPCs and host retinal cells following subretinal injection into a rodent model of RP, revealing dynamic transcriptomic changes in the degenerative retinal environment. Grafted hNPCs primarily differentiate into an astroglial phenotype and mature over time, contributing to photoreceptor protection through trophic factor secretion, metabolic modulation, suppression of apoptosis, oxidative stress, and inflammation, alongside extracellular matrix remodeling. CellChat analysis revealed a decline in intercellular signaling and communication strength over time, correlating with weakened hNPC-host interactions. These findings suggest that enhancing trophic factor support, particularly MANF, and improving the host retinal environment are critical for sustaining long-term vision preservation.人神经前体细胞（human neural progenitor cells，hNPCs）在延缓视网膜变性方面展现出良好应用前景，目前正针对色素性视网膜炎（retinitis pigmentosa，RP）开展临床试验。然而，移植的hNPCs的长期存活命运及其与宿主视网膜细胞的相互作用机制仍不明确。本研究采用单细胞转录组学（single-cell transcriptomics）技术，对色素性视网膜炎啮齿动物模型实施视网膜下注射移植实验，分析移植的hNPCs与宿主视网膜细胞的时序基因表达变化，揭示了变性视网膜微环境中的动态转录组改变。研究发现，移植的hNPCs主要分化为星形胶质细胞表型并随时间推移逐步成熟，通过分泌神经营养因子、调控代谢、抑制细胞凋亡、氧化应激与炎症反应，以及重塑细胞外基质，发挥光感受器保护作用。通过CellChat分析可知，细胞间信号传导与通讯强度随时间逐渐下降，该现象与hNPC与宿主细胞的相互作用减弱呈显著相关。上述研究结果表明，增强神经营养因子支持（尤其是中脑星形胶质细胞源性神经营养因子（mesencephalic astrocyte-derived neurotrophic factor，MANF））并改善宿主视网膜微环境，对于长期维持视力保护效果至关重要。