Lung Self-Assembly Is Modulated by Tissue Surface Tensions

To identify cell-intrinsic properties that facilitate interaction between epithelial endodermal and mesenchymal mesodermal cells during lung morphogenesis, we developed a model of lung self-assembly that mimics fetal lung formation in structure, polarity, vasculature, and extracellular matrix expression. Three-dimensional pulmonary bodies (PBs) spontaneously self-assemble from single-cell suspensions and exhibit liquid-like properties that allow measurements of compaction rate and cohesion, and that may help to specify cellular self-organization. We hypothesized that changes in one or more of these parameters could potentially explain the lung hypoplasia associated with abnormal lung development. We examined the impact of endothelial/monocyte–activating polypeptide (EMAP) II in PBs, because EMAPII is highly expressed in lung hypoplasia. EMAPII significantly increased compaction rate and decreased overall cohesion of PBs composed of both epithelial and mesenchymal cells. Moreover, the effects of EMAPII on compaction and cohesion act exclusively through the mesenchymal cell population by interfering with fibronectin matrix assembly. We also show that EMAPII alters epithelial cell polarity and surfactant protein C expression. Our findings demonstrate, for the first time, that PBs possess liquid-like properties that can help to guide the self-assembly of fetal lungs, and that EMAPII expression can influence both mesenchymal and epithelial cells but through different molecular mechanisms.