Abstract
Damage to alveoli, the gas-exchanging region of the lungs, is a component of many chronic and acute lung diseases. In addition, insufficient generation of alveoli results in bronchopulmonary dysplasia, a disease of prematurity. Therefore visualising the process of alveolar development (alveologenesis) is critical for our understanding of lung homeostasis and for the development of treatments to repair and regenerate lung tissue. Here we show live alveologenesis, using long-term, time-lapse imaging of precision-cut lung slices. We reveal that during this process, epithelial cells are highly mobile and we identify specific cell behaviours that contribute to alveologenesis: cell clustering, hollowing and cell extension. Using the cytoskeleton inhibitors blebbistatin and cytochalasin D, we show that cell migration is a key driver of alveologenesis. This study reveals important novel information about lung biology and provides a new system in which to manipulate alveologenesis genetically and pharmacologically.
Highlights
Damage to alveoli, the gas-exchanging region of the lungs, is a component of many chronic and acute lung diseases
Using Precision Cut Lung Slice imaging (PCLSi), combined with pharmacological inhibitors of the actin-myosin cytoskeleton, we show that epithelial cell migration plays a dominant role in early alveologenesis
We have established a method for visualising murine alveologenesis in real time
Summary
The gas-exchanging region of the lungs, is a component of many chronic and acute lung diseases. Detailed knowledge of airway generation, which occurs in utero, prior to alveolarisation, has been gained from both static and ex vivo real-time imaging experiments because counterintuitively, mouse embryonic lungs are both practically and experimentally more accessible[9,10,11]. Sacculation begins at embryonic day (E) 17.5, lasting until the first few days of postnatal life[1] During this stage, the primitive air sacs form from the distal airways and distal tip epithelial cells begin to express markers indicative of their differentiation into mature type I (ATI) and type II (ATII) alveolar epithelial cells, such as podoplanin and pro-surfactant protein C (SP-C) respectively. Based on inference from static images, it is thought that alveoli form by repeated septation events that sub-divide primitive airspaces thereby increasing the surface area for gas exchange[12,18]. Cell migration is believed to be important in alveologenesis, for septation to occur, but it has not been possible to confirm the relative contributions of migration and proliferation until now
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