Full Text | PDF

Theranostics 2024; 14(4):1500-1516. doi:10.7150/thno.92943 This issue Cite

Research Paper

Transfer RNA derived fragment, tRF-Glu-CTC, aggravates the development of neovascular age-related macular degeneration

Yu Liang^1,2,3,*, Lingjie Kong^1,2,3,*, Yuelu Zhang^1,2,3,*, Yihan Zhang^1,2,3,*, Mingsu Shi^1,2,3, Jiaqiu Huang^1,2,3, Hongyu Kong^1,2,3, Siyi Qi^1,2,3, Yunlong Yang⁴, Jiaxu Hong^1,2,3, Meidong Zhu^5,6, Xiangjia Zhu^1,2,3, Xinghuai Sun^1,2,3, Shujie Zhang^1,2,3✉, Lianqun Wu^1,2,3✉, Chen Zhao^1,2,3✉

1. Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, 83 Fenyang Road, Shanghai, 200031, China.
2. NHC Key Laboratory of Myopia (Fudan University); Key Laboratory of Myopia, Chinese Academy of Medical Sciences, 83 Fenyang Road, Shanghai, 200031, China.
3. Shanghai Key Laboratory of Visual Impairment and Restoration, 83 Fenyang Road, Shanghai, 200031, China.
4. Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
5. Save Sight Institute, Discipline of Clinical Ophthalmology and Eye Health, University of Sydney, Camperdown, NSW 2000, Australia.
6. New South Weals Tissue Bank, New South Weals Organ and Tissue Donation Service, Sydney Eye Hospital, 8 Macquarie Street, Sydney 2000, Australia.
^*These authors contributed equally.

✉ Corresponding authors: Shujie Zhang, PhD. Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, 83 Fenyang Road, Shanghai, 200031, China; E-mail: shujiezhangedu.cn. Lianqun Wu, MD, PhD. Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, 83 Fenyang Road, Shanghai, 200031, China; E-mail: lianqun.wuorg. Chen Zhao, MD, PhD. Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, 83 Fenyang Road, Shanghai, 200031, China; E-Mail: dr_zhaochenedu.cn. More

Abstract

Rationale: Angiogenesis expedites tissue impairment in many diseases, including age-related macular degeneration (AMD), a leading cause of irreversible blindness in elderly. A substantial proportion of neovascular AMD patients, characterized by aberrant choroidal neovascularization (CNV), exhibit poor responses or adverse reactions to anti-VEGF therapy. Herein, we aimed to unveil the function of newly identified transfer RNA-derived small RNA, tRF-Glu-CTC, in the pathology of CNV and determine its potential in inhibiting angiogenesis.

Methods: Small non-coding RNA sequencing and quantitative polymerase chain reaction were conducted to detect expression pattern of tRF-Glu-CTC in CNV development. Immunofluorescence staining, fundus fluorescein angiography and ex vivo choroidal sprouting assays were employed for the evaluation of tRF-Glu-CTC's function in CNV development. The role of tRF-Glu-CTC in endothelial cells were determined by in vitro endothelial cell proliferation, migration and tube formation assays. Transcriptome sequencing, dual-luciferase reporter assay and in vitro experiments were conducted to investigate downstream mechanism of tRF-Glu-CTC mediated pathology.

Results: tRF-Glu-CTC exhibited substantial up-regulation in AMD patients, laser-induced CNV model, and endothelial cells under hypoxia condition, which is a hallmark of CNV. Inhibiting tRF-Glu-CTC reduced angiogenesis and hypoxia stress in the neovascular region without neuroretina toxicity in laser-induced CNV model, showing an anti-angiogenic effect comparable to bevacizumab, while overexpression of tRF-Glu-CTC significantly augmented CNV. Mechanically, under hypoxia condition, angiogenin was involved in the production of tRF-Glu-CTC, which in turn triggered endothelial cell tubulogenesis, migration and promoted the secretion of inflammatory factors via the suppression of vasohibin 1 (VASH1). When downregulating VASH1 expression, the inhibition of tRF-Glu-CTC showed minimal suppression on angiogenesis.

Conclusions: This study demonstrated the important role of tRF-Glu-CTC in the progression of angiogenesis. Targeting of tRF-Glu-CTC may be an alternative to current anti-VEGF therapy for CNV in AMD and other conditions with angiogenesis.

Keywords: Age-related macular degeneration, choroidal neovascularization, tRNA-derived small noncoding RNAs, angiogenesis

Citation styles

©2024 Ivyspring International Publisher. Terms of use