Abstract
Introduction: Chronic lung diseases, such as pulmonary fibrosis, are linked to aging and exhibit hallmarks of aging, including cellular senescence and mitochondrial dysfunction. WNT/β-catenin signaling has been implicated in fibrotic lung epithelial cell reprogramming, however, the underlying mechanism remains under-investigated.
Aims: Here, we aim to identify cell-specific mechanisms of how chronic WNT/β-catenin leads to lung epithelium reprogramming.
Methods: Single-cell RNA sequencing (scRNA-Seq) of precision-cut lung slices subjected to acute and chronic WNT/β-catenin signaling was performed. Mitochondria metabolism and function was assessed by mtDNA content, biogenesis and transcriptional control analyzed by qPCR, Immunofluorescence (IF) and Western Blotting.
Results: scRNA-seq revealed altered mitochondrial signaling and function in distinct lung epithelial cell populations, such as alveolar type II (ATII) cells, upon chronic WNT stimulation. These findings were further validated and expanded upon using WNT/β-catenin stimulated primary ATII cells, which showed a significant decrease in mtDNA content with a concomitant decrease in mitochondrial function as measured by TOMM20 IF. Furthermore, PGC1a, the regulator of mitochondrial biogenesis, was decreased by chronic but not acute WNT signaling. More upstream, the transcription factor myc was decreased upon chronic WNT activation.
Conclusion: Unbiased scRNA-Seq identified impaired mitochondrial function upon chronic WNT/β-catenin stimulation in lung epithelial cells. Chronic WNT stimulation, which is present in the aged and fibrotic lung led to disturbed mitochondrial biogenesis by downregulating the myc-PGC1a axis in lung epithelial cells.
Footnotes
Cite this article as: European Respiratory Journal 2021; 58: Suppl. 65, OA2699.
This abstract was presented at the 2021 ERS International Congress, in session “Prediction of exacerbations in patients with COPD”.
This is an ERS International Congress abstract. No full-text version is available. Further material to accompany this abstract may be available at www.ers-education.org (ERS member access only).
- Copyright ©the authors 2021