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

Abstract

ArticlePremature newborns often suffer from hypoxemia and acute respiratory failure. Supplemental oxygen is one of the most treatments for preterm respiratory support. It has been reported that prolonged exposure to hyperoxia results in oxidative stress-induced tissue damage in the lung, such as acute lung injury and bronchopulmonary dysplasia (BPD) (Kugelman and Durand 2011). BPD is a clinical syndrome of chronic respiratory, which can lead to hypoxemic respiratory failure and death. Advance in mechanical ventilation increases the percentage of infants surviving delivery earlier in gestation but also results in a high morbidity of BPD (Merritt et al. 2009).In animal models, retarded lung alveolization and differentiation of alveolar epithelial type II cells (AECIIs), fewer and larger alveoli, and enlarged airspace area were found in hyperoxia-exposed lungs (Dauger et al. 2003;Wang et al. 2005;Woyda et al. 2009). These damages were considered the result of the decreased proliferation of alveolar epithelium. Alveoli are lined by two morphologically and functionally different types of cells, type I alveolar epithelial cells (AECIs) and type II alveolar epithelial cells (AECIIs) (Crapo et al. 1982). AECIs cover 95% to 99% of the alveolar surface area and are responsible for gas, ions, SummaryThe 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 β-catenin. In addition, Wnt3a/β-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/β-catenin signal may be involved in the hyperoxiainduced inhibition of AECIIs' transdifferentiation to AECIs. (J Histochem Cytochem 63:879-891, 2015)

YAP and Wnt3a independently promote AECIIs proliferation and differentiation by increasing nuclear β‑catenin expression in experimental bronchopulmonary dysplasia

“…The present study thus aimed to determine the role of YAP in the proliferation and differentiation of AECIIs and the involvement of the Wnt/β-catenin pathway in this process in BPD. It was demonstrated that YAP expression was decreased in experimental BPD and played a key role in promoting the proliferation and differentiation of AECIIs, consistent with a previous study by the authors on Wnt3a ( 23 ). In addition, it was found that Wnt3a overexpression could compensate for YAP depletion and vice versa; however, neither altered the expression of the other.…”

“…Previously, the authors reported that Wnt signaling plays key roles in alveolar injury and repair by regulating the proliferation and differentiation of AECIIs ( 22 , 23 ). The Wnt signaling pathway consists of both canonical and noncanonical pathways ( 24 ) involving Wnt proteins, receptors and regulatory factors that control numerous biological processes, including cell proliferation, development and differentiation ( 25 , 26 ).…”

In vitro modelling of alveolar repair at the air-liquid interface using alveolar epithelial cells derived from human induced pluripotent stem cells

“…These findings on the effect of CHIR99021 are in apparent contrast to a recent mouse study, which suggested that Wnt signalling is required to maintain stemness of AEC2 cells, and that Wnt signalling prevents transdifferentiation of AEC2 40,41 . In addition, Xu et al previously showed that the canonical Wnt ligand Wnt3a blocked transdifferentiation of AEC2 to AEC1 42 . To add to the complexity of Wnt signalling during generation of hiPSC-derived AEC2, it was demonstrated that temporary withdrawal of CHIR99021 is associated with iAEC2 maturation 23,39 , whereas maintenance of proliferation requires adding back CHIR99021 39 .…”

Linking bronchopulmonary dysplasia to adult chronic lung diseases: role of WNT signaling

“…Nuclear translocation of β-catenin and increased Lef1 expression was observed in the lung from neonatal rats exposed to hyperoxia (95 % oxygen) in the alveolar stage (postnatal days 0 to 7) [ 82 ]. Moreover, it has been shown that neonatal hyperoxia increased nuclear β-catenin and decreased alveolar epithelial type II (ATII) cell to ATI cell transdifferentiation [ 84 , 92 ], which is generally considered as a repair process of alveolar epithelial cells following injury. Furthermore, hyperoxia-induced inhibition of ATII to ATI transdifferentiation was recovered by small interfering RNA (siRNA)-mediated knockdown of Wnt3a in vitro [ 92 ].…”

“…Moreover, it has been shown that neonatal hyperoxia increased nuclear β-catenin and decreased alveolar epithelial type II (ATII) cell to ATI cell transdifferentiation [ 84 , 92 ], which is generally considered as a repair process of alveolar epithelial cells following injury. Furthermore, hyperoxia-induced inhibition of ATII to ATI transdifferentiation was recovered by small interfering RNA (siRNA)-mediated knockdown of Wnt3a in vitro [ 92 ]. However, it has been reported that in the adult mouse lung, β-catenin was induced during ATII cell to ATI cell transdifferentiation in normoxia condition [ 93 , 94 ].…”