Developmental Origins of Chronic Lung Diseases. Mechanical Stretch, Micro-RNAs, and Hydrogels.

The primary function of the lungs is to exchange oxygen with carbon dioxide between the external environment and the internal cardiovascular system. Although seemingly straightforward, the development of a fully functional lung is fraught with challenges. To successfully undergo growth and maturation, the lungs develop through five well-orchestrated stages (2). Despite extensive work over the past decades, mechanisms through which mechanical forces contribute to epithelial differentiation and alveologenesis remain incompletely understood. Using mouse genetics, live imaging, and quantitative cell biology, Li and colleagues (1) demonstrated that mechanical forces act synergistically with local growth factors to drive alveolar epithelial cell differentiation. By aspirating amniotic fluid from mouse embryo yolk sacs, creating a condition of “oligoamnios,” the authors found that mechanical forces generated by inhalation of amniotic fluid are essential for alveolar epithelial type 1 (AT1) cell differentiation. When compared with lungs from littermate controls at Embryonic Day 18.5, terminal sac opening and cell shape flattening of AT1 cells were impaired in oligoamnios-treated embryos as assessed by immunostaining and time-sequenced imaging. The lack of AT1 differentiation was accompanied by a compensatory increase in AT2 epithelial cells, suggesting that mechanical stretch has less impact on AT2 cell differentiation than on AT1 cells. Secondarily, the authors explored cellular processes associated with saccular dilation and epithelial cell differentiation. Interestingly, the authors observed basal protrusions from cuboidal-shaped airway tip cells before alveolar formation. These cellular protrusions were actin based and extended into the adjacent mesenchyme. Over time, epithelial cells with basal protrusions constricted, as assessed by phosphorylated nonmuscle myosin light chain II, remained cuboidal in shape, and ultimately differentiated into AT2. Conversely, cells without basal protrusions became thinner and flattened over time, and differentiated into AT1 cells. To examine the mechanism underlying the development of these basal protrusions, the investigators used genetic mice and chemical inhibitors of fibroblast growth factor (FGF) 10. In the heterozygous FGF10 embryos or after chemical FGF10 inhibition in wild-type embryos, the number of progenitor cells with protrusions decreased, suggesting that protrusion and its associated mesenchymal connection were FGF10 dependent. These findings have significant clinical implications for children with developmental or chronic lung disease after preterm birth. Oligohydramnios and insufficient lung stretch contribute to pulmonary hypoplasia, especially in the setting of prolonged premature rupture of membranes before preterm birth and with diverse congenitalmalformations as omphaloceles and congenital diaphragmatic hernia, at least partly due to the lack of mechanical force–induced stimulation of AT1 cell differentiation (3, 4). For some fetuses with congenital diaphragmatic hernia, an in utero procedure, called fetoscopic endotracheal occlusion, is used to obstruct the trachea with a latex balloon (5). By occluding the trachea, airway-distending pressures are increased owing to ongoing epithelial production of lung liquid, which stretches the distal lung and stimulates AT1 and AT2 cell maturation (4). The fetoscopic endotracheal occlusion procedure likely improves survival through forced lung maturation by mechanical stretch (5), as suggested by this study. Despite the significant advances made by Li and colleagues (1), interrogating the effect of mechanical forces on other essential cells in lung development, specifically stromal and endothelial cells