IPF lung resident mesenchymal stem cells differentiate into epithelial cells displaying a disease-specific transcriptome

Rationale: Repetitive injury to alveolar epithelial cells in idiopathic pulmonary fibrosis (IPF) is the initial step activating interstitial fibroblasts and their enhanced ECM production, leading to progressive lung fibrosis. A new therapeutic approach in IPF may therefore aim to replace damaged epithelial cells. Lung resident mesenchymal stem cells (MSC) differentiate into epithelial cells in vitro. Here, we characterized MSC-derived epithelial progeny of IPF and non-IPF fibrotic lung diseases and determined possible disease-specific differences in their transcriptome. Methods: Differentiation of cultured MSC was initiated and progeny analysed by immunofluorescence, TaqMan PCR or next generation sequencing. Results: Typical morphology, visualized through F-actin, and positive E-cadherin staining identified MSC progeny as epithelial cells. RNA and protein expression of p63, keratin 5, and SOX2 suggested that MSC progeny may be epithelial progenitor cells, which was supported by the RNA sequencing data confirming canonical lung epithelial cell- and progenitor cell marker expression. The transcriptome of MSC progeny revealed significant disease-specific differences, with 779 genes down- and 678 genes up-regulated in IPF progeny. Furthermore, proliferation-associated pathways were enriched, whereas cytokine signalling was reduced during the process of differentiation. Conclusion: IPF and non-IPF lung resident MSC differentiate into epithelial progenitor-like cells with a disease specific transcriptomic landscape. Assessing the functional role and potential therapeutic use of MSC and their progeny in IPF will be of interest for future studies.