The aim of the present study was to characterize pulmonary fibroblast subtypes regarding differentiation and localization during alveolarization and to reveal the impact of fibroblast function on alveolarization. A further aim was to validate and characterize a previously generated Cre driver mouse line to target lipofibroblasts and the further usage of this mouse line to target lipofibroblasts in vivo. To address these aims, using in vivo tools of the CreERT2 stop loxP system and reporter genes, the present study demonstrated that platelet-derived growth factor receptor &
alpha;+ (PDGFR&
alpha;+) cells of the early postnatal period could give rise to myofibroblasts and lipofibroblasts during alveolarization. Furthermore, markers of mesenchymal stem cells were detected in generated myo- and lipo-fibroblasts, supporting the progenitor cell character of PDGFR&
alpha;+ cells. Consequently, the depletion of early postnatal PDGFR&
alpha;+ cells caused a disruption of alveolarization resulting in an abnormal lung structure. This proves the need of PDGFR&
#945;+ cells for proper alveolarization. The present study further validated and characterized the inducible function to target lipofibroblasts of a recently generated Plin2tm1.1(Cre/ERT2)Mort mouse line. Using this functional validated mouse line the present study revealed the spatiotemporal mode of differentiation of lipofibroblasts during alveolarization by labeling and characterizing cells of the ADRP cell-lineage. Finally using the Plin2tm1.1(Cre/ERT2)Mort mouse line it was demonstrated for the first time, that the early postnatal ADRP cell-lineage (lipofibroblast lineage) is essential for appropriate alveolarization. Data of the present study give new insights into the differentiation and function of fibroblast subtypes during alveolarization and provide a new tool to target and manipulate lipofibroblasts in vivo by validating the previously generated Cre driver line. The study makes a new contribution to the identification of cellular and molecular targets for the development of new therapeutic strategies for pulmonary structural diseases since the induction of alveolarization in the diseased lung represents a desirable therapeutic approach.
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