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hMSCs-derived exosome circCDK13 inhibits liver fibrosis by regulating the expression of MFGE8 through miR-17-5p/KAT2B

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Abstract

Objective

To investigate the effects of human bone marrow mesenchymal stem cells (hMSCs)-derived exosome circCDK13 on liver fibrosis and its mechanism.

Methods

Exosomes derived from hMSCs were extracted and identified by flow cytometry and osteogenic and adipogenic induction, and the expressions of marker proteins on the surface of exosomes were detected by western blot. Cell proliferation was measured by CCK8 assay, the expression of active markers of HSCs by immunofluorescence, and the expressions of fibrosis-related factors by western blot. A mouse model of liver fibrosis was established by intraperitoneal injection of thioacetamide (TAA). Fibrosis was detected by HE staining, Masson staining, and Sirius red staining. Western blot was utilized to test the expressions of PI3K/AKT and NF-κB pathway related proteins, dual-luciferase reporter assay and RIP assay to validate the binding between circCDK13 and miR-17-5p as well as between miR-17-5p and KAT2B, and ChIP to validate the effect of KAT2B on H3 acetylation and MFGE8 transcription.

Results

hMSCs-derived exosomes inhibited liver fibrosis mainly through circCDK13. Dual-luciferase reporter assay and RIP assay demonstrated the binding between circCDK13 and miR-17-5p as well as between miR-17-5p and KAT2B. Further experimental results indicated that circCDK13 mediated liver fibrosis by regulating the miR-17-5p/KAT2B axis, and KAT2B promoted MFGE8 transcription by H3 acetylation. Exo-circCDK13 inhibited PI3K/AKT and NF-κB signaling pathways activation through regulating the miR-17-5p/KAT2B axis.

Conclusion

hMSCs-derived exosome circCDK13 inhibited liver fibrosis by regulating the expression of MFGE8 through miR-17-5p/KAT2B axis.

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Data availability

The datasets used or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

Thanks for the grants from National Key R&D Program of China (No. 2019YFE0190800); Key R&D Program of Hunan province (No. 2020SK2083); the National Natural Science Foundation of China (No. 81500455 ); the National Natural Science Foundation of China (No. 81974079); the National Natural Science Foundation of China (No. 82070646) and Hunan Provincial Health Commission (No. 202120700992).

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Authors and Affiliations

  1. Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, People’s Republic of China

    Jing Ma, Yi Li, Mengxuan Chen, Weihang Wang, Qiqian Zhao, Bo He, Min Zhang & Yongfang Jiang

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  1. Jing Ma
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  2. Yi Li
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  3. Mengxuan Chen
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  4. Weihang Wang
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  5. Qiqian Zhao
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  6. Bo He
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  7. Min Zhang
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  8. Yongfang Jiang
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Contributions

MJ and JYF conceived the ideas. MJ and JYF designed the experiments. JYF and LY performed the experiments. LY and CMX analyzed the data. CMX, WWH, and ZQQ provided critical materials. HB and ZM wrote the manuscript. MJ supervised the study. All the authors have read and approved the final version for publication.

Corresponding author

Correspondence to Yongfang Jiang.

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Conflict of interest

The authors declare no competing interests.

Ethics approval and consent to participate

All experimental procedures involving animal were conducted with the consent of Institutional Animal Care and Use Committee of the Second Xiangya Hospital.

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Highlights

• CircCDK13 inhibits liver fibrosis at the cellular and animal levels.

• CircCDK13 targets and binds miR-17-5p, while miR-17-5p targets KAT2B.

• CircCDK13 regulates liver fibrosis by regulating the miR-17-5p/KAT2B axis.

• CircCDK13 affects MFGE8 by regulating miR-17-5p/KAT2B axis to regulate liver fibrosis.

• CircCDK13 inhibits PI3K/AKT and NF-κB pathways by regulating miR-17-5p/KAT2B axis.

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Ma, J., Li, Y., Chen, M. et al. hMSCs-derived exosome circCDK13 inhibits liver fibrosis by regulating the expression of MFGE8 through miR-17-5p/KAT2B. Cell Biol Toxicol 39, 1–22 (2023). https://doi.org/10.1007/s10565-022-09714-4

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  • DOI: https://doi.org/10.1007/s10565-022-09714-4

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