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单细胞 RNA 测序：高度近视中增加的晶状体纤维细胞分化的基础是 Notch2 信号抑制。

Single-cell RNA sequencing: Inhibited Notch2 signalling underlying the increased lens fibre cells differentiation in high myopia.

机构信息

Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, China.

National Health Center Key Laboratory of Myopia (Fudan University), Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, China.

出版信息

Cell Prolif. 2023 Aug;56(8):e13412. doi: 10.1111/cpr.13412. Epub 2023 Jan 30.

DOI:10.1111/cpr.13412
PMID:36717696
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10392066/
Abstract

High myopia is the leading cause of blindness worldwide. It promotes the overgrowth of lens, which is an important component of ocular refractive system, and increases the risks of lens surgery. While postnatal growth of lens is based on the addition of lens fibre cells (LFCs) supplemented by proliferation and differentiation of lens epithelial cells (LECs), it remains unknown how these cellular processes change in highly myopic eyes and what signalling pathways may be involved. Single-cell RNA sequencing was performed and a total of 50,375 single cells isolated from the lens epithelium of mouse highly myopic and control eyes were analysed to uncover their underlying transcriptome atlas. The proportion of LFCs was significantly higher in highly myopic eyes. Meanwhile, Notch2 signalling was inhibited during lineage differentiation trajectory towards LFCs, while Notch2 predominant LEC cluster was significantly reduced in highly myopic eyes. In consistence, Notch2 was the top down-regulated gene identified in highly myopic lens epithelium. Further validation experiments confirmed NOTCH2 downregulation in the lens epithelium of human and mouse highly myopic eyes. In addition, NOTCH2 knockdown in primary human and mouse LECs resulted in enhanced differentiation towards LFCs accompanied by up-regulation of MAF and CDKN1C. These findings indicated an essential role of NOTCH2 inhibition in lens overgrowth of highly myopic eyes, suggesting a therapeutic target for future interventions.

摘要

高度近视是全球致盲的主要原因。它会促进晶状体的过度生长，而晶状体是眼球屈光系统的重要组成部分，增加了晶状体手术的风险。虽然晶状体的出生后生长是基于晶状体纤维细胞（LFCs）的添加，这些细胞通过晶状体上皮细胞（LECs）的增殖和分化得到补充，但仍不清楚高度近视眼中这些细胞过程是如何变化的，以及可能涉及哪些信号通路。我们进行了单细胞 RNA 测序，共从高度近视和对照小鼠的晶状体上皮中分离出 50375 个单细胞进行分析，以揭示其潜在的转录组图谱。高度近视眼中 LFCs 的比例明显更高。同时，Notch2 信号在向 LFCs 的谱系分化轨迹中被抑制，而高度近视眼中 Notch2 占主导地位的 LEC 簇明显减少。一致地，Notch2 是在高度近视晶状体上皮中鉴定出的下调幅度最大的基因。进一步的验证实验证实了人类和小鼠高度近视眼中晶状体上皮中的 NOTCH2 下调。此外，在原代人源和鼠源 LECs 中敲低 NOTCH2 会导致向 LFCs 的分化增强，同时 MAF 和 CDKN1C 的表达上调。这些发现表明 NOTCH2 抑制在高度近视眼中晶状体过度生长中起重要作用，提示这可能是未来干预的治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fa4b/10392066/b565c6900de5/CPR-56-e13412-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fa4b/10392066/418d9db317ab/CPR-56-e13412-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fa4b/10392066/32fe702fae43/CPR-56-e13412-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fa4b/10392066/b62254f9b796/CPR-56-e13412-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fa4b/10392066/781f348434a9/CPR-56-e13412-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fa4b/10392066/ddf859d5f8c6/CPR-56-e13412-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fa4b/10392066/b565c6900de5/CPR-56-e13412-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fa4b/10392066/418d9db317ab/CPR-56-e13412-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fa4b/10392066/32fe702fae43/CPR-56-e13412-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fa4b/10392066/b62254f9b796/CPR-56-e13412-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fa4b/10392066/781f348434a9/CPR-56-e13412-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fa4b/10392066/ddf859d5f8c6/CPR-56-e13412-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fa4b/10392066/b565c6900de5/CPR-56-e13412-g006.jpg

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