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Epo inhibits the fibrosis and migration of Müller glial cells induced by TGF-β and high glucose

  • Basic Science
  • Published:
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Abstract

Background

In proliferative diabetic retinopathy (PDR), Müller glial cells (MGCs) acquire migratory ability and exhibit a fibroblast-like phenotype. These activated MGCs contribute to the formation of epiretinal membrane, which will stretch the retina, and cause retinal detachment and vitreous hemorrhage. Erythropoietin (Epo) is now found effective in ameliorating renal fibrosis by inhibiting epithelial-to-mesenchymal transition of tubular epithelial cells. This study is undertaken to determine whether Epo has an effect in inhibiting MGCs activation to attenuate epiretinal membrane formation in PDR.

Method

MIO-M1 cell line was used in this study. As a pilot test to determine the most efficient treatment time and concentration of Epo, levels of connective tissue growth factor (CTGF) and transforming growth factor-β (TGF-β) were measured by real-time PCR, after treatment with Epo on MGCs cultured in high glucose. MGCs were cultured in high glucose and normal glucose for 2 days, with or without TGF-β as a pro-fibrogenic cytokine. Epo was introduced at the same time. Immunofluorescence targeting α-smooth muscle actin (α-SMA), fibronectin, and glial fibrillary acidic protein (GFAP) was performed to explore the cell phenotype. Matrix metalloproteinase 9 (MMP9) mRNA level was detected by real-time PCR. Protein levels of CTGF and cytoskeletal proteins like α-SMA and fibronectin were measured by enzyme-linked immunosorbent assay (ELISA) and Western blot respectively. Wound-healing assay was applied to evaluate the migratory ability of MGCs, and actin-tracker green was used to draw the structure of F-actin in MGCs.

Results

After being seeded into high-glucose medium containing TGF-β, MGCs expressed a larger amount of MMP9 mRNA as well as α-SMA, fibronectin at protein level. They secreted more CTGF, and their F-actin reorganized in a parallel manner and showed a stronger ability to migrate. In addition, these changes, including mRNA and protein expression, F-actin assembling, and cell migration, could be attenuated significantly by Epo treatment.

Conclusion

High glucose together with TGF-β promote MGCs to exhibit a fibroblast-like phenotype and develop a greater migratory ability. These changes can be inhibited by Epo, which therefore may contribute to the controlling of epiretinal membrane formation.

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Acknowledgments

The authors thank H Li and Ch Sun for their assistance throughout the study and JF Zhang for critical review of the manuscript.

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Authors and Affiliations

  1. Department of Ophthalmology, Shanghai Tenth People’s Hospital, Tongji University, Shanghai, China

    Wentao Luo, Liumei Hu, Linxinyu Xu, Conghui Zhang & Fang Wang

  2. Department of Ophthalmology, Drexel University College of Medicine, Philadelphia, PA, USA

    Weiye Li

  3. Department of Ophthalmology of Shanghai Tenth People’s Hospital and Tongji Eye Institute, Tongji University School of Medicine, Shanghai, China

    Guotong Xu

  4. Department of Regenerative Medicine and Stem Cell Research Center, Tongji University School of Medicine, Shanghai, China

    Guotong Xu

  5. Institute for Nutritional Sciences, Tongji University School of Medicine, Shanghai, China

    Guotong Xu

  6. Department of Ophthalmology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, 301 Yanchang Road, 15th floor, Building 1, Shanghai, 200071, China

    Fang Wang

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  1. Wentao Luo
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Correspondence to Fang Wang.

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Funding

The National Nature Science Foundation of China provided financial support in the form of the National Nature Science Funding (Grant No.81200693).

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All authors certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge, or beliefs) in the subject matter or materials discussed in this manuscript.

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Wentao Luo and Liumei Hu contributed equally to the work presented here and should therefore be regarded as equal authors.

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Luo, W., Hu, L., Li, W. et al. Epo inhibits the fibrosis and migration of Müller glial cells induced by TGF-β and high glucose. Graefes Arch Clin Exp Ophthalmol 254, 881–890 (2016). https://doi.org/10.1007/s00417-016-3290-5

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