The role of mesenchymal cells in developmental alveologenesis and alveolar repair during lung regeneration

• Applicant: Professor Elie El Agha, Ph.D.
• Subject Area: Pneumology, Thoracic Surgery ; Developmental Biology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 458065839

Pulmonary diseases are among the leading causes of death worldwide and most of these devastating diseases lack preventive or curative therapy. In particular, pathogen-induced lung injury is a serious threat to global health and influenza virus or coronavirus outbreaks can lead to pandemics resulting in millions of deaths worldwide. The aim of the proposed research project is to characterize and dissect the role of mesenchymal cells during developmental alveologenesis and alveolar repair during lung regeneration. The lung mesenchyme is believed to control morphogenesis during embryonic lung development and drive or at least provide permissive signals for postnatal alveolar septation, the process of subdivision of primitive alveolar sacs into smaller functional alveoli. The involvement of mesenchymal cells in lung regeneration is largely unexplored although the literature suggests that developmental programs are likely reactivated or recapitulated in such conditions. In this proposal, mesenchymal cells will be characterized using genetic lineage tracing, which is the gold-standard method for dissecting cellular hierarchy, in combination with confocal imaging of thick lung sections (followed by 3D reconstruction) and transcriptional profiling at the single-cell level during developmental alveologenesis and alveolar repair after injury. These investigations will inform about the underlying cellular heterogeneity and the signaling pathways that are active in these cells in the context of various physiological and pathological settings. Selective genetic cell ablation will also be carried out in order to test the requirement of these cells for lung regeneration. Finally, patient-derived material will be used to test the significance of the findings in human lung disease. Taken together, this project will improve our understanding of the basic mechanisms involved in alveologenesis at the cellular and molecular levels and establish whether a similar developmental program is active in the repairing lung.

• DFG Programme: Research Grants