Examining the role of Notch signaling in dysplastic lung repair

Severe lung injury promotes the appearance of ectopic basal cells in the alveolar space. Since these cells appear to contribute to barrier restoration but demonstrate very inefficient differentiation into normal alveolar epithelium, this represents a dysplastic repair response. Prior work demonstrated the necessity of Notch signaling for expansion of these cells directly as well as indirectly via interactions with activated fibroblasts, but the original studies largely relied on γ-secretase inhibitors which lack specificity for the Notch pathway. Here we utilize a genetic, dominant-negative approach to more carefully assess the role of Notch signaling in these prior studies. Using transgenic mice expressing a dominant-negative (dn) MAML construct, our data supports the interpretation that Notch signaling to dysplastic cells impacts their expansion post-influenza. However, dnMAML expression at later time points did not appreciably increase differentiation into alveolar epithelial cells. These results confirm earlier studies and reiterate the advantages of genetic approaches to directly inhibit Notch over less specific pharmacological approaches.