PD-L1 Promotes Immunological Tolerance and Enhances Visual Protection of hESC-RPE Grafts in Retinal Degeneration.

IF 5.9 1区生物学 Q2 CELL BIOLOGY Cell Proliferation Pub Date : 2025-02-14 DOI:10.1111/cpr.70007

Bowen Li, Xue Zhang, Yajie Fang, Min Chen, Qiyou Li, Yuxiao Zeng, Chunge Ren, Chengang Wang, Yingxue Lv, Jia Lu, Hongling Liu, Yong Liu

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Abstract

Immune rejection is a major barrier to the successful human embryonic stem cell-derived retinal pigment epithelial (hESC-RPE) transplantation for age-related macular degeneration (AMD). Traditional strategies to mitigate immune rejection involve ablating major histocompatibility complex (MHC) molecules on hESC-RPE. An alternative approach is immune checkpoint overexpression, avoiding natural killer (NK) cell-mediated destruction due to MHC-I deficiency. Our study highlights the benefits of PD-L1 overexpression without requiring MHC gene deletion, which preserved the immunosuppressive functions of hESC-RPE on NK cells. In Vivo experiments in retinal degeneration models showed that PD-L1-expressing hESC-RPE grafts exhibited significantly higher survival, reduced apoptosis and enhanced visual protection. Single-cell transcriptomics revealed reduced immune activation and oxidative stress in PD-L1-overexpressing grafts. PD-L1's protective role was further evidenced by improved light transduction in host photoreceptors. These findings support PD-L1 overexpression as a promising strategy to improve the efficiency of hESC-RPE-based therapy for AMD.

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免疫排斥是人类胚胎干细胞衍生视网膜色素上皮（hESC-RPE）移植治疗老年性黄斑变性（AMD）成功的主要障碍。减轻免疫排斥反应的传统策略包括消融hESC-RPE上的主要组织相容性复合体（MHC）分子。另一种方法是免疫检查点过度表达，以避免自然杀伤（NK）细胞因 MHC-I 缺乏而介导的破坏。我们的研究强调了 PD-L1 过度表达的好处，无需删除 MHC 基因，就能保留 hESC-RPE 对 NK 细胞的免疫抑制功能。视网膜变性模型的体内实验表明，表达 PD-L1 的 hESC-RPE 移植物存活率显著提高，凋亡减少，视觉保护能力增强。单细胞转录组学显示，PD-L1表达移植物的免疫激活和氧化应激减少。宿主光感受器中光传导的改善进一步证明了PD-L1的保护作用。这些研究结果支持将 PD-L1 过表达作为提高基于 hESC-RPE 的 AMD 治疗效率的一种有前途的策略。

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来源期刊

Cell Proliferation 生物-细胞生物学

CiteScore

14.80

自引率

2.40%

发文量

198

审稿时长

1 months

期刊介绍： Cell Proliferation Focus: Devoted to studies into all aspects of cell proliferation and differentiation. Covers normal and abnormal states. Explores control systems and mechanisms at various levels: inter- and intracellular, molecular, and genetic. Investigates modification by and interactions with chemical and physical agents. Includes mathematical modeling and the development of new techniques. Publication Content: Original research papers Invited review articles Book reviews Letters commenting on previously published papers and/or topics of general interest By organizing the information in this manner, readers can quickly grasp the scope, focus, and publication content of Cell Proliferation.

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