Wnt3a Mediates the Inhibitory Effect of Hyperoxia on the Transdifferentiation of AECIIs to AECIs

The aim of this study is to investigate the effect of Wnt3a in the transdifferentiation of type II alveolar epithelial cells (AECIIs) to type I alveolar epithelial cells (AECIs) under hyperoxia condition. In the in vivo study, preterm rats were exposed in hyperoxia for 21 days. In the in vitro study, primary rat AECIIs were subjected to a hyperoxia and normoxia exposure alternatively every 24 hr for 7 days. siRNA-mediated knockout of Wnt3a and exogenous Wnt3a were used to investigate the effect of Wnt3a on transdifferentiation of AECIIs to AECIs. Wnt5a-overexpressed AECIIs were also used to investigate whether Wnt3a could counteract the effect of Wnt5a. The results showed that hyperoxia induced alveolar damage in the lung of preterm born rats, as well as an increased expression of Wnt3a and nuclear accumulation of -catenin. In addition, Wnt3a/-catenin signaling was activated in isolated AECIIs after hyperoxia exposure. Wnt3a knockout blocked the inhibition of the transdifferentiation induced by hyperoxia, and Wnt3a addition exacerbated this inhibition. Furthermore, Wnt3a addition blocked the transdifferentiation-promoting effect of Wnt5a in hyperoxia-exposed Wnt5a-overexpressed AECIIs. In conclusion, our results demonstrate that the activated Wnt3a/-catenin signal may be involved in the hyperoxia-induced inhibition of AECIIs' transdifferentiation to AECIs.