Defining the mesenchymal niche in airway epithelial regeneration

• Applicant: Professor Elie El Agha, Ph.D.
• Subject Area: Pneumology, Thoracic Surgery ; Developmental Biology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 507879190

The respiratory system is regularly challenged by pathogens, toxins and other irritants. In response to epithelial injury, the lung is capable of mobilizing stem and progenitor cells to repair the denuded epithelium and restore barrier function. Such cells, however, depend on microenvironmental cues and interaction with other cells that constitute the stem cell niche, particularly mesenchymal cells. Club cells are dome-shaped, non-ciliated secretory cells that are characterized by the expression of secretoglobin family 1A member 1 (SCGB1A1). Following naphthalene-mediated club cell depletion, surviving variant club cells located at neuroepithelial bodies or bronchioalveolar duct junctions mediate the repair process in the bronchial epithelium. Previous work has indicated that these cells closely interact with (or at least with a subset of) airway smooth muscle cells (ASMCs) that produce FGF10. We have recently identified a novel mesenchymal niche population that we termed repair-supportive mesenchymal cells (RSMCs). In that work, we used genetic lineage tracing and organoid cultures to show that these cells 1) are in close vicinity to ASMCs in the confined peribronchial space, 2) transit through the smooth muscle lineage and 3) produce FGF10. The aim of the current grant proposal is to better define such mesenchymal niche by understanding how heterogeneous the RSMC population is, and whether these cells are relevant for human lung disease. To achieve this, we will use novel, recently generated, genetic mouse tools as well as state of the art in vitro functional assays. Human lung material will also be employed.

• DFG Programme: Research Grants