Role of mitochondrial function of lung mesenchymal stem cells in idiophatic pulmonary fibrosis

[eng] Introduction: Idiopathic pulmonary fibrosis (IPF) is an age-related disease which consists in several damage in the lung due to an abundant scarring, deposition of extracellular matrix proteins and inflammation. Mesenchymal stem cells (MSC) play a role in tissue repair, however the involvement of resident MSC in IPF aetiology remains to be elucidated. Preliminary microarray analysis revealed that the most altered pathway in IPF MSC is oxidative phosphorylation. The aim of this study is to analyse mitochondrial function-related features and the repair activity of IPF lung MSC. Material and methods: Human lung MSC from non-IPF and IPF patients will be used in cell culture assays. RT-PCR was used to study COX4, ATP6, PGC1-α and PINK1 expression levels, and ddPCR to estimate mitochondrial number. Mitochondrial membrane potential assay was set-up in the present work to evaluate mitochondrial integrity in lung MSC. Scratch assays was performed to analyse the ability of lung MSCs to repair damage in both direct and indirect coculture with epithelial A549 cells. Results: Compared to non-IPF cells, IPF MSC presented lower COX4 and PINK1 expression, similar mitochondrial membrane potential in the presence of TGF-β, and a delayed repair activity in both direct and indirect coculture systems, which was only evidenced in serumrestricted conditions. TGF-β incubation stimulated the repair activity of both IPF and non-IPF MSC, but the increase was more pronounced in IPF cells. TGF-β-incubated IPF MSC presented lower COX4, ATP6 and PINK1 expression, and TGF-β treatment induced the expression of the migration marker VEGF. Conclusion: The impaired repair activity of IPF MSC is associated with signs of mitochondrial dysfunction, and this activity is more sensitive to TGF-β. TGF-β, in turn, induces mitochondrial dysfunction in IPF MSC. Collectively, these results suggest that the overproduction of TGF-β in the fibrotic lung may impair the repair activity of resident MSC by inducing mitochondrial dysfunction, which deserves further investigation