Long-term PM2.5 exposure disrupts corneal epithelial homeostasis by impairing limbal stem/progenitor cells in humans and rat models.

IF 7.2 1区医学 Q1 TOXICOLOGY Particle and Fibre Toxicology Pub Date : 2023-09-27 DOI:10.1186/s12989-023-00540-y

Shengjie Hao, Zhijian Chen, Yuzhou Gu, Lu Chen, Feiyin Sheng, Yili Xu, Di Wu, Yu Han, Bing Lu, Shuying Chen, Wei Zhao, Houfa Yin, Xiaofeng Wang, S Amer Riazuddin, Xiaoming Lou, Qiuli Fu, Ke Yao

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Abstract

Background: Limbal stem/progenitor cells (LSPCs) play a crucial role in maintaining corneal health by regulating epithelial homeostasis. Although PM2.5 is associated with the occurrence of several corneal diseases, its effects on LSPCs are not clearly understood.

Methods: In this study, we explored the correlation between PM2.5 exposure and human limbal epithelial thickness measured by Fourier-domain Optical Coherence Tomography in the ophthalmologic clinic. Long- and short-term PM2.5 exposed-rat models were established to investigate the changes in LSPCs and the associated mechanisms.

Results: We found that people living in regions with higher PM2.5 concentrations had thinner limbal epithelium, indicating the loss of LSPCs. In rat models, long-term PM2.5 exposure impairs LSPCs renewal and differentiation, manifesting as corneal epithelial defects and thinner epithelium in the cornea and limbus. However, LSPCs were activated in short-term PM2.5-exposed rat models. RNA sequencing implied that the circadian rhythm in LSPCs was perturbed during PM2.5 exposure. The mRNA level of circadian genes including Per1, Per2, Per3, and Rev-erbα was upregulated in both short- and long-term models, suggesting circadian rhythm was involved in the activation and dysregulation of LSPCs at different stages. PM2.5 also disturbed the limbal microenvironment as evidenced by changes in corneal subbasal nerve fiber density, vascular density and permeability, and immune cell infiltration, which further resulted in the circadian mismatches and dysfunction of LSPCs.

Conclusion: This study systematically demonstrates that PM2.5 impairs LSPCs and their microenvironment. Moreover, we show that circadian misalignment of LSPCs may be a new mechanism by which PM2.5 induces corneal diseases. Therapeutic options that target circadian rhythm may be viable options for improving LSPC functions and alleviating various PM2.5-associated corneal diseases.

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在人类和大鼠模型中，长期接触PM2.5会损害角膜缘干/祖细胞，从而破坏角膜上皮稳态。

背景：角膜缘干/祖细胞（LSPCs）通过调节上皮稳态在维持角膜健康方面发挥着至关重要的作用。尽管PM2.5与几种角膜疾病的发生有关，但其对LSPCs的影响尚不清楚。方法：在本研究中，我们探讨了PM2.5暴露与眼科临床傅里叶域光学相干断层扫描测量的人角膜缘上皮厚度之间的相关性。建立了长期和短期暴露于PM2.5的大鼠模型，以研究LSPCs的变化及其相关机制。结果：我们发现生活在PM2.5浓度较高地区的人角膜缘上皮较薄，这表明LSPCs的损失。在大鼠模型中，长期暴露于PM2.5会损害LSPCs的更新和分化，表现为角膜上皮缺陷和角膜和角膜缘上皮变薄。然而，LSPCs在短期PM2.5暴露的大鼠模型中被激活。RNA测序表明，在PM2.5暴露期间，LSPCs的昼夜节律受到干扰。在短期和长期模型中，包括Per1、Per2、Per3和Rev-erbα在内的昼夜节律基因的mRNA水平均上调，这表明昼夜节律在不同阶段参与了LSPCs的激活和失调。PM2.5还扰乱了角膜缘微环境，角膜基底下神经纤维密度、血管密度和通透性以及免疫细胞浸润的变化证明了这一点，这进一步导致了LSPCs的昼夜节律不匹配和功能障碍。结论：本研究系统地证明了PM2.5损害了LSPCs及其微环境。此外，我们发现LSPCs的昼夜节律失调可能是PM2.5诱导角膜疾病的一种新机制。针对昼夜节律的治疗方案可能是改善LSPC功能和缓解各种PM2.5相关角膜疾病的可行方案。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Particle and Fibre Toxicology TOXICOLOGY-

CiteScore

15.90

自引率

4.00%

发文量

审稿时长

6 months

期刊介绍： Particle and Fibre Toxicology is an online journal that is open access and peer-reviewed. It covers a range of disciplines such as material science, biomaterials, and nanomedicine, focusing on the toxicological effects of particles and fibres. The journal serves as a platform for scientific debate and communication among toxicologists and scientists from different fields who work with particle and fibre materials. The main objective of the journal is to deepen our understanding of the physico-chemical properties of particles, their potential for human exposure, and the resulting biological effects. It also addresses regulatory issues related to particle exposure in workplaces and the general environment. Moreover, the journal recognizes that there are various situations where particles can pose a toxicological threat, such as the use of old materials in new applications or the introduction of new materials altogether. By encompassing all these disciplines, Particle and Fibre Toxicology provides a comprehensive source for research in this field.