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TFAM-Mediated mitochondrial transfer of MSCs improved the permeability barrier in sepsis-associated acute lung injury

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Abstract

Vascular endothelial cell barrier disruption is a hallmark of sepsis-induced acute lung injury (ALI). Mesenchymal stem cells (MSCs)-based therapy has been regarded as a promising treatment for repairing injured lungs, and mitochondrial transfer was shown to be important for the therapeutic effects of MSCs. Here we investigated the ability of MSCs to modulate endothelial barrier integrity through mitochondrial transfer in sepsis-induced ALI. We found that mitochondrial transfer from MSCs to LPS-induced PMVECs through forming tunneling nanotubes (TNTs). Due to the inhibition of TNTs (using LAT-A), MSCs-mediated reparation on PMVECs functions, including cell apoptosis, MMP, ATP generation, TEER level and monolayer permeability of FITC-dextran were greatly inhibited. In addition, silencing of mitochondrial transcription factor A (TFAM) in MSCs could also partly inhibit the TNTs formation and aggravate the LPS-induced mitochondrial dysfunction and permeability barrier in PMVECs. Furthermore, the LPS-induced pulmonary edema and higher pulmonary vascular permeability were alleviated by MSCs while that of lung tissue bounced back after MSCs were pre-incubated by LAT-A and or down-regulation of TFAM. Therefore, we firstly revealed that regulation of TFAM expression in MSCs played a critical role to improve the permeability barrier of PMVECs by TNTs mediating mitochondrial transfer in sepsis-associated ALI. This study provided a new therapeutic strategy for the treatment of sepsis-induced ALI.

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Data availability

The data reported in this study are available from the corresponding author (yinhaiyan1867@126.com) upon reasonable request.

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Acknowledgements

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Funding

This study was supported by grants from the National Natural Science Foundation of China (NO. 82072232 and NO.81871585), the Natural Science Foundation of Guangdong Province (NO. 2018A030313058), the Medical Scientific Research Foundation of Guangdong Province, China (NO.A2021176) and the Planned Science and Technology project of Guangzhou, China (NO. 201804010308).

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Authors and Affiliations

  1. Department of Intensive Care Unit, the First Affiliated Hospital of Jinan University, No.613, West Huangpu Avenue, Guangzhou, 510630, Guangdong, China

    Feng Zhang, Xinglong Zheng, Fengzhi Zhao, Longzhu Li, Yinlong Ren, Lijun Li, Haiyan Huang & Haiyan Yin

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  1. Feng Zhang
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  2. Xinglong Zheng
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  3. Fengzhi Zhao
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  5. Yinlong Ren
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  6. Lijun Li
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  7. Haiyan Huang
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  8. Haiyan Yin
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Contributions

Haiyan Yin participated in study design. Feng Zhang and Xinglong Zheng made the experiments. Fengzhi Zhao made the statistical analysis. Longzhu Li and Lijun Li assisted with data analysis. Feng Zhang prepared the manuscript, and Yinlong Ren and Haiyan Huang assisted with literature search. Haiyan Yin provided the financial support.

Corresponding author

Correspondence to Haiyan Yin.

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All the animal experiments were undertaken in accordance with the National Institute of Health Guide for the Care and Use of laboratory Animals with approval from the Animal Ethics Committee of the First Affiliated Hospital of Jinan university.

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All authors declare having no conflict of interest related to this research.

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Feng Zhang and Xinglong Zheng Contributed equally.

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Zhang, F., Zheng, X., Zhao, F. et al. TFAM-Mediated mitochondrial transfer of MSCs improved the permeability barrier in sepsis-associated acute lung injury. Apoptosis 28, 1048–1059 (2023). https://doi.org/10.1007/s10495-023-01847-z

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