Characterization of AT2 and LIF Heterogeneity and Role of Fgf10/Fgfr2b Signaling in the Maintenance of Adult Lung Homeostasis - Importance of Reciprocal Lipofibroblast/AT2 Stem Cell Interactions

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This proposal will investigate the interaction between Lipofibroblasts (LIFs) and Alveolar type 2 cells (AT2s). The hypothesis that will be tested is that Fibroblast growth factor 10, produced by a specific subtype of lipofibroblasts (which will be defined) acts via Fgfr2b expressed in alveolar type epithelial cells. The heterogeneity of the LIFs and the alveolar epithelial lineage will be investigated using lineage tracing with already generated and innovative recombinase-based transgenic animals (Aim 1). The role of Fgfr2b in the alveolar epithelial lineage during aging will be carried out using Fgfr2bflox mice (cell autonomous approach; Aim 2). We will also inactivate Fgf10 expression in the lipofibroblasts using Fgf10flox mice (Aim 3) and characterize the capacity of LIF in young (P81) and old (P378) mice to maintain young AT2 cells using alveolospheres. We will also test the capacity of young and old AT2 cell to respond to young LIF (Aim 4). We will finally investigate the regenerative role of recombinant FGF10 on new alveoli formation in homeostatic and diseased condition (mouse model of bronchopulmonary dysplasia) (Aim 5). Our proposal will abundantly rely on the human biobank in Giessen to validate observations made in mice for the epithelial alveolar lineage. We will also take advantage of fibroblasts isolated from the lung aspirates of BPD patients to test the function of different compounds on the differentiation of the fibroblasts along the LIF lineage. Overall, the results generated through this proposal will enhance our understanding of the cellular and molecular mechanisms involved in lung homeostasis and repair after injury.