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Involvement of METTL3/m6Adenosine and TGFβ/Smad3 signaling on Tenon’s fibroblasts and in a rabbit model of glaucoma surgery

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Abstract

Glaucoma filtration surgery (GFS) is a classic operation for the treatment of glaucoma, which is the second leading cause of blindness, and scar formation caused by excessive human Tenon’s capsule fibroblasts (HTFs) activation is responsible for surgery failure. However, the mechanism underlying excessive HTFs activation is largely unknown. Studies have revealed that N6-methyladenosine (m6A), which is one of the most common posttranscriptional modifications, plays an important role in multiple types of cellular processes. First, we isolated and identified primary HTFs and found that transforming growth factor-β1 (TGF-β1) enhanced cell viability and promoted cell proliferation and extracellular matrix (ECM) deposition in HTFs. We subsequently found that TGF-β1 elevated the quantity of m6A and promoted the expression of m6A “writers”, in the process from DNA to RNA, adenylate was methylated at the sixth N position by methylases methyltransferase-like 3 (METTL3). Furthermore, we demonstrated that METTL3 repression inhibited the promotion of cell viability, proliferation and ECM deposition in HTFs treated with TGF-β1. We then illustrated that increased METTL3 played a role by promoting Smad3 in TGF-β1-induced HTFs. We subsequently demonstrated that the METTL3/Smad3 regulatory axis was aberrantly expressed in the rabbit model of GFS. Thus, our study reveals that METTL3 indeed plays a role in modulating Smad3 in TGF-β1-induced HTFs and further provides novel theoretical strategies based on METTL3 for the inhibition of scar formation after GFS.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 81570841).

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Authors and Affiliations

  1. Department of Ophthalmology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China

    Yan Liu, Chao Gu & Ling Yu

  2. Department of Pathology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China

    Xiabin Li

  3. Department of Ophthalmology, Army Medical Center, Daping Hospital, Army Medical University, Chongqing, 400042, China

    Tingwei Wang

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  1. Yan Liu
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LY designed the experiments; LY, YL, CG, XBL and TWW conducted the experiments; LY and YL analyzed the data and wrote the paper. All authors have read and approved the manuscript.

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Correspondence to Ling Yu.

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Liu, Y., Gu, C., Li, X. et al. Involvement of METTL3/m6Adenosine and TGFβ/Smad3 signaling on Tenon’s fibroblasts and in a rabbit model of glaucoma surgery. J Mol Histol 52, 1129–1144 (2021). https://doi.org/10.1007/s10735-021-10028-8

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  • DOI: https://doi.org/10.1007/s10735-021-10028-8

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