Lung resident mesenchymal stem cells in idiopathic pulmonary fibrosis

Current evidence suggests that lung resident mesenchymal stem cells (LRMSC) contribute to idiopathic pulmonary fibrosis (IPF) by differentiating into myofibroblasts. Our transcriptomic analysis supported this since mesenchyme development and collagen metabolism were two different biological processes between IPF and control LRMSC [1]. Despite this, the role of LRMSC in IPF is far from being resolved. To explore the ability of IPF LRMSC to acquire myofibroblast features in vitro and to promote lung fibrosis in bleomycin (BLM)-treated mice. Gene expression was assessed by RT-PCR and western blot. In vitro, LRMSC were treated with TGFβ at 1, 10 or 20ng/ml. In vivo, IPF or control LRMSC, or vehicle were inoculated in mice 48h after 2U/kg BLM or PBS instillation. Mice were sacrificed at day 14. IPF LRMSC expressed extracellular matrix proteins and α-smooth muscle actin at the mRNA and protein levels in basal conditions. TGFβ responses in the expression of acta2, collagen, fibronectin, and tenascin were significantly higher in control vs IPF LRMSC. In vivo, IPF and control LRMSC-inoculated did not affect BLM-induced histological and molecular signs of lung fibrosis and inflammation. Moreover, within BLMtreated mice, cytokeratin-8 and -18 protein levels were higher (P<0.05) in control vs IPF LRMSC-inoculated mice. Further in vitro characterization revealed an impaired regenerative activity, mitochondrial dysfunction, and an altered expression of senescence and pro-apoptotic markers in IPF LRMSC. Our results do not support that IPF LRMSC promote lung fibrosis. Stem cell exhaustion and other signs of accelerated aging may prevail in LRMSC from established IPF. [1]Mercader-Barceló, J. et al. Cells 2023; 12(16), 2084.