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Bone marrow mesenchymal stem cells-induced exosomal microRNA-486-3p protects against diabetic retinopathy through TLR4/NF-κB axis repression

Journal of Endocrinological Investigation volume 44, pages 1193–1207 (2021)Cite this article

Abstract

Aim

Diabetic retinopathy (DR) is a chronic disease causing health and economic burdens on individuals and society. Thus, this study is conducted to figure out the mechanisms of bone marrow mesenchymal stem cells (BMSCs)-induced exosomal microRNA-486-3p (miR-486-3p) in DR.

Methods

The putative miR-486-3p binding sites to 3′untranslated region of Toll-like receptor 4 (TLR4) was verified by luciferase reporter assay. High glucose (HG)-treated Muller cells were transfected with miR-486-3p or TLR4-related oligonucleotides and plasmids to explore theirs functions in DR. Additionally, HG-treated Muller cells were co-cultured with BMSC-derived exosomes, exosomes collected from BMSCs that had been transfected with miR-486-3p or TLR4-related oligonucleotides and plasmids to explore their functions in DR. MiR-486-3p, TLR4 and nuclear factor-kappaB (NF-κB) expression, angiogenesis-related factors, oxidative stress factors, viability and apoptosis in HG-treated Muller cells were detected by RT-qPCR, western blot analysis, ELISA, MTT assay and flow cytometry, respectively.

Results

MiR-486-3p was poorly expressed while TLR4 and NF-κB were highly expressed in HG-treated Muller cells. TLR4 was a target of miR-486-3p. Upregulating miR-486-3p or down-regulating TLR4 inhibited oxidative stress, inflammation and apoptosis, and promoted proliferation of HG-treated Muller cells. Meanwhile, BMSC-derived exosomes inhibited oxidative stress, inflammation and apoptosis, and promoted proliferation of HG-treated Muller cells. Restoring miR-486-3p further enhanced, while up-regulating TLR4 reversed, the improvement of exosomes treatment.

Conclusion

Our study highlights that up-regulation of miR-486-3p induced by BMSC-derived exosomes played a protective role in DR mice via TLR4/NF-κB axis repression.

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Acknowledgements

We would like to acknowledge the reviewers for their helpful comments on this paper.

Funding

The current research was funded by Medical Science and Technology Research fund project of Guangdong Province (Grant/Award number: B2018139).

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Affiliations

  1. Department of Ophthalmology, The Second Clinical Medical College of Jinan University, Shenzhen People’s Hospital, 1017 Dongmen North Road, Luohu District, Shenzhen, 518000, Guangdong, China

    W. Li, L. Jin, Y. Cui, A. Nie & N. Xie

  2. Department of Ophthalmology, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, 53300, Guangxi, China

    G. Liang

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  1. W. Li
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  2. L. Jin
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  3. Y. Cui
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  4. A. Nie
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  5. N. Xie
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Correspondence to N. Xie or G. Liang.

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All animal experiments were carried out with the approval of the ethics committee of The Second Clinical Medical College of Jinan University, Shenzhen People's Hospital and the uses of animals were in strict conformity with the International Code of Ethics and the National Health Guidelines on the Maintenance and Use of Laboratory Animals.

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Li, W., Jin, L., Cui, Y. et al. Bone marrow mesenchymal stem cells-induced exosomal microRNA-486-3p protects against diabetic retinopathy through TLR4/NF-κB axis repression. J Endocrinol Invest 44, 1193–1207 (2021). https://doi.org/10.1007/s40618-020-01405-3

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  • DOI: https://doi.org/10.1007/s40618-020-01405-3

Keywords

  • Diabetic retinopathy
  • MicroRNA-486-3p
  • Bone marrow mesenchymal stem cells
  • Exosomes
  • Toll-like receptor 4
  • NF-κb signaling pathway