Heterogeneity of human corneal endothelium implicates lncRNA NEAT1 in Fuchs endothelial corneal dystrophy.
Heterogeneity of human corneal endothelium implicates lncRNA NEAT1 in Fuchs endothelial corneal dystrophy.
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人角膜内皮的异质性表明lncRNA NEAT1与Fuchs内皮性角膜营养不良有关
DOI：
10.1016/j.omtn.2022.01.005
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发表时间：
2022-03-08
期刊：
影响因子：
--
通讯作者：
Shi W
中科院分区：
文献类型：
--
作者：
Wang Q;Dou S;Zhang B;Jiang H;Qi X;Duan H;Wang X;Dong C;Zhang BN;Xie L;Cao Y;Zhou Q;Shi W
角膜内皮通过屏障和泵功能介导水合作用，对维持角膜透明度至关重要。角膜内皮细胞在衰老过程中的进行性损失与Fuchs角膜内皮营养不良（FECD）的发展相关，这是角膜相关视力丧失的主要原因之一。发展幼儿发展的基本机制仍然难以捉摸。对分离的健康人角膜进行单细胞RNA测序，发现了4个具有独特特征的角膜内皮细胞亚群。无监督聚类分析发现核富集丰富的转录本1（NEAT 1），一个长的非编码RNA（lncRNA），作为最高表达的基因在C 0-内皮细胞亚群，但显着下调FECD。与人角膜一致，UVA诱导的小鼠FECD模型验证了NEAT 1表达的丧失。通过体内遗传方法丧失NEAT 1功能，通过消融角膜内皮细胞再现了FECD的加重表型。相反，通过CRISPR激活的腺病毒递送系统获得的功能保护角膜免受UVA诱导的FECD。我们的研究结果为FECD的发展提供了新的机制见解，靶向NEAT 1为治疗FECD提供了一种有吸引力的方法。没有治愈性疗法可用于有效治疗FECD，这是一种与年龄相关的复杂遗传性疾病。Wang等人鉴定了NEAT 1，一种在FECD中强烈下调的lncRNA，作为FECD发展中的关键调节因子，其通过rAAV CRISPR系统的过表达延迟了FECD的发作和进展。
The corneal endothelium is critical for maintaining corneal clarity by mediating hydration through barrier and pump functions. Progressive loss of corneal endothelial cells during aging has been associated with the development of Fuchs endothelial corneal dystrophy (FECD), one of the main causes of cornea-related vision loss. The mechanisms underlying FECD development remain elusive. Single-cell RNA sequencing of isolated healthy human corneas discovered 4 subpopulations of corneal endothelial cells with distinctive signatures. Unsupervised clustering analysis uncovered nuclear enriched abundant transcript 1 (NEAT1), a long non-coding RNA (lncRNA), as the top expressed gene in the C0-endothelial subpopulation, but markedly downregulated in FECD. Consistent with human corneas, a UVA-induced mouse FECD model validated the loss of NEAT1 expression. Loss of NEAT1 function by an in vivo genetic approach reproduced the exacerbated phenotype of FECD by ablating corneal endothelial cells. Conversely, gain of function by a CRISPR-activated adenoviral delivery system protected corneas from UVA-induced FECD. Our findings provide novel mechanistic insights into the development of FECD, and targeting NEAT1 offers an attractive approach for treating FECD. No curative therapy is available for effectively treating FECD, an age-related complex genetic disorder. Wang et al. identified NEAT1, a lncRNA strongly downregulated in FECD, as a key regulator in development of FECD, whose overexpression by the rAAV CRISPR system delayed the onset and progression of FECD.
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