The role of lung lipofibroblasts in alveolar differentiation

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Abstract A complication of preterm birth is underdeveloped lungs that lack surfactant and adequate gas exchange due to immature alveoli. Although recent advances have been made, the process of alveolar maturation is not well understood. A goal of this project is to understand signaling from mesenchymal cells that direct alveologenesis, the final stage of lung development. We have found that disruption of a specialized fibroblast, the lipofibroblast, results in reduced type II alveolar cell differentiation. Type II alveolar cells are responsible for surfactant production, and we will investigate the communication between lipofibroblasts and alveolar cells during lung development in the mouse. The lipofibroblast has been a difficult cell to identify, and little is known about the function of these cells. Our preliminary data demonstrate that a transcription factor is required for the development of lipofibroblasts and alveolar differentiation. Based upon these preliminary findings, we hypothesize that lipofibroblasts are required for the later steps of lung development and that they secrete growth factors that are required specifically for terminal differentiation of type II alveolar cells. We will investigate these cellular interactions in two specific aims. In specific aim I, we will determine how lipofibroblasts impact alveolar differentiation by examining the temporal requirement for lipofibroblasts and by evaluating postnatal lung development in mice lacking lipofibroblasts. In Specific Aim II we will use in vitro organoid culture and gene expression profiling to explore the lipofibroblast cellular signals that direct type II alveolar differentiation. Together these aims will define the role of the lipofibroblast and potentially identify therapeutic targets for increasing the rate of type II alveolar differentiation in preterm births.