Efficient intervention for pulmonary fibrosis via mitochondrial transfer promoted by mitochondrial biogenesis

Ting Huang, Ruyi Lin, Yuanqin Su, Hao Sun, Xixi Zheng, Jinsong Zhang, Xiaoyan Lu, Baiqin Zhao, Xinchi Jiang, Lingling Huang, Ni Li, Jing Shi, Xiaohui Fan, Donghang Xu, Tianyuan Zhang () and Jianqing Gao ()
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Ting Huang: Zhejiang University
Ruyi Lin: Zhejiang University
Yuanqin Su: Zhejiang University
Hao Sun: Zhejiang University
Xixi Zheng: Zhejiang University
Jinsong Zhang: Zhejiang University
Xiaoyan Lu: Zhejiang University
Baiqin Zhao: Zhejiang University School of Medicine
Xinchi Jiang: Zhejiang University
Lingling Huang: Zhejiang University School of Medicine
Ni Li: Ningbo University
Jing Shi: Hangzhou Medical College
Xiaohui Fan: Zhejiang University
Donghang Xu: Zhejiang University School of Medicine
Tianyuan Zhang: Zhejiang University
Jianqing Gao: Zhejiang University

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract The use of exogenous mitochondria to replenish damaged mitochondria has been proposed as a strategy for the treatment of pulmonary fibrosis. However, the success of this strategy is partially restricted by the difficulty of supplying sufficient mitochondria to diseased cells. Herein, we report the generation of high-powered mesenchymal stem cells with promoted mitochondrial biogenesis and facilitated mitochondrial transfer to injured lung cells by the sequential treatment of pioglitazone and iron oxide nanoparticles. This highly efficient mitochondrial transfer is shown to not only restore mitochondrial homeostasis but also reactivate inhibited mitophagy, consequently recovering impaired cellular functions. We perform studies in mouse to show that these high-powered mesenchymal stem cells successfully mitigate fibrotic progression in a progressive fibrosis model, which was further verified in a humanized multicellular lung spheroid model. The present findings provide a potential strategy to overcome the current limitations in mitochondrial replenishment therapy, thereby promoting therapeutic applications for fibrotic intervention.

Date: 2023
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DOI: 10.1038/s41467-023-41529-7

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