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Priming epithelial cell activation to regenerate the lung

Final Report Summary - PEARL (Priming epithelial cell activation to regenerate the lung)

Chronic obstructive pulmonary disease (COPD), a global health problem, will be the third leading cause of death by 2020. No effective therapy exists for COPD, which is characterized by a progressive loss of lung tissue, in particular functional lung epithelium, due to the inability of the lung to regenerate.
The overall aim of this project was to explore the regenerative potential of the adult human lung, driven by the alveolar epithelium. As a potential therapeutic target, we focused on the WNT/β-catenin signal pathway, which is crucial for normal lung development, reduced in COPD lungs and thus is a promising initiating factor for lung regeneration. Within the project, we generated and established ex vivo 3D-lung tissue cultures (3D-LTCs), in which it is possible to visualize diseased lung tissue of patients in 3D with high spatio-temporal resolution. We were able to demonstrate for the first time that WNT/β-catenin activation is achievable in diseased patient derived 3D-LTCs and correlates with disease stage. Moreover, we further investigated the cause of reduced WNT/β-catenin signaling in COPD and identified novel potential therapeutic targets for differentiation that complement WNT/β-catenin activation and thus further drive the regenerative process.
Alltogether, this project led to the identification of novel targets that initiate and drive lung regenerative processes. The 3D-LTCs represent a valuable tool to close the gap that formerly existed between target identification and preclinical validation of drug compounds and their application in the era of precision medicine.