Cellular and molecular mediators of alveolar septum formation and regeneration
Final Report Abstract
The present project aimed to identify and characterize cellular and molecular candidates which crucially regulate alveolar septum formation. Understanding of the process of septum formation is necessary to find new possible targets for regenerative therapeutic strategies of pulmonary structural diseases. Most important scientific progress of the current project was achieved by successfully generating transgenic mouse lines (ADRPCreERT/mCherry and the ADFP/tTA-YFP) as a basis for further lineage tracing and loss of function analysis of the lipofibroblast population. Lipofibroblasts are abundant distributed during lung development and during the process of alveolarization. They support alveolar type 2 cell function. Thus they represent an interstitial cell type which might be important for the integrity and regenerative capacity of the alveolar compartment. The transgenic mouse lines which were generated in cooperation with M. Szibor and T. Braun are essential for functional in vivo analysis of the lipofibroblast function. Next, the identification of PDGFRα positive cells as precursor cells of lipo- and myofibroblasts respectively depending on the different stages of lung development represents an important step within the characterization of fibroblast subsets during alveologenesis. Further functional analysis are needed to validate these cells as target candidates for regenerative therapeutical strategies but there function as progenitor cells has been shown by lineage tracing for the first time. Most surprising appeared the fact that only a part of the lipofibroblast pool was generated from PDGFRα positive precursor cells. This was not expected since previous loss of function analysis of PDGFRα showed a strong pulmonary phenotype with emphysema like structure. Finally a striking scientific progress in understanding of septum formation was achieved through the data on Shh loss of function analysis. They demonstrated a strong impact of Shh in septum formation since Shh knock out and pharmacological inhibition lead to a severe disruption of alveolar structure. Even the connection between Shh and fibroblast function could be demonstrated. Therefore Shh represents a further important target candidate for new regenerative therapeutical strategies. Taken together the present project added some new insights into the understanding of the process of septum formation. Therefore it contributed to some progress towards the identification of cellular and molecular targets for regenerative therapies of structural pulmonary diseases.
