Effects of LATS1/2 kinases inhibition on lung epithelial cells in a regeneration model

Research focused on studying Hippo signaling up- and downregulation in a model of mouse lung cell regeneration. The cell-specific role of the activation and inhibition of Hippo signaling is demonstrated at the cellular level within the context of a unified bronchoalveolar lung organoid model. We used pharmacological modulators of Hippo pathway components-TRULI and verteporfin. The findings revealed that inhibition of Lats1/2 kinases via TRULI leads to different levels of Hippo gene expression for different lung cell types. The inhibition of Lats1/2 kinases enhances cell proliferation in the bronchiolar epithelium, while verteporfin suppresses it. However, no changes in the cellular composition of the bronchiolar epithelium (except ciliated cells) were observed with either TRULI or verteporfin. Inhibition of Lats1/2 kinases in the alveolar epithelium leads to a decrease in type 2 alveolocytes and alters their differentiation trajectories. The results demonstrate a cell-specific influence of Hippo modulation on the lung cells and may prove useful for the development of novel therapeutic approaches for the treatment of respiratory pathologies.