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

Abstract

Arrested alveolar development is the main pathological characteristic of neonatal bronchopulmonary dysplasia (BPD); however, a number of studies aiming to improve alveolarization have focused on alveolar epithelial cell damage and impairment. Previously, the authors reported that the Wnt signaling plays a key role in alveolar injury and repair by regulating alveolar epithelial type II cell (AECII) proliferation and differentiation. In the present study, the authors wished to investigate whether Yes-associated protein (YAP), a transcriptional coactivator in the Hippo signaling pathway, affects AECII proliferation and differentiation via the Wnt/β-catenin pathway in BPD. It was found that YAP regulated AECII proliferation and differentiation. A decreased expression of YAP, Wnt3a and nuclear β-catenin was observed in lung tissues affected by BPD. In vitro , YAP and Wnt3a overexpression in BPD promoted AECII proliferation and differentiation into AECIs by increasing the nuclear transfer of β-catenin and vice versa. The effects of a decreased Wnt3a expression in primary AECIIs in BPD were compensated by YAP overexpression, as were the effects of Wnt3a knockdown in primary AECIIs. On the whole, the findings of the present study demonstrate that YAP and Wnt3a independently promote AECII proliferation and differentiation in experimental BPD by increasing the nuclear β-catenin levels. Therefore, Wnt3a or YAP may be candidate regulatory targets for improving the outcomes of BPD.

Hippo signaling pathway and respiratory diseases

“…The respiratory epithelial cells of mature lung are stationary under normal physiological conditions, but a variety of epithelial cells, such as type II alveolar epithelial cells (AECIIs) and basal cells, significantly regenerate when lung is injured [ 58 – 60 ]. It is reported that the YAP improves the self-renewal of AECIIs and the differentiation of AECIIs into type I alveolar epithelial cells (AECIs) with lung injury [ 59 , 61 , 62 ]. In addition, YAP is essential for AECIIs proliferating or differentiating into AECIs in response to mechanical tension [ 59 , 61 , 63 , 64 ].…”

“…It is reported that the YAP improves the self-renewal of AECIIs and the differentiation of AECIIs into type I alveolar epithelial cells (AECIs) with lung injury [ 59 , 61 , 62 ]. In addition, YAP is essential for AECIIs proliferating or differentiating into AECIs in response to mechanical tension [ 59 , 61 , 63 , 64 ]. In the process of alveolar regeneration, AECIIs responds to the increase of mechanical forces outside the environment, which lead to the aggregation and the activation of YAP in nucleus and promote the proliferation of AECIIs as well as the differentiation of the AECIIs into AECIs [ 59 , 61 , 63 , 64 ].…”

“…In addition, YAP is essential for AECIIs proliferating or differentiating into AECIs in response to mechanical tension [ 59 , 61 , 63 , 64 ]. In the process of alveolar regeneration, AECIIs responds to the increase of mechanical forces outside the environment, which lead to the aggregation and the activation of YAP in nucleus and promote the proliferation of AECIIs as well as the differentiation of the AECIIs into AECIs [ 59 , 61 , 63 , 64 ]. In addition, lung microvascular endothelial cells (LMVECs) release sphingosine-1-phosphate (S1P), which plays an important role in regulating the progenitor function of AECIIs during the repair of alveolar epithelial [ 65 ].…”

A small molecule modulating monounsaturated fatty acids and Wnt signaling confers maintenance to induced pluripotent stem cells against endodermal differentiation

“…For instance, Wnt protein activation, intra-cellular and extra-cellular transportation, and binding to cell surface receptors are dependent on MUFA residues. In previous studies, the critical role of Wnt3a, as the main member of the Wnt family, has been documented in the niche of stem cells [ 11 – 13 ]. Like other members of the Wnt cascade, Wnt3a can transfer signaling to downstream effectors, such as the β-catenin/canonical pathway after MUFA-mediated interaction with cell surface receptors.…”

Hyperoxia-Exposed Lung Injury Upregulates DVL-1 Protein Expression And Activates Wnt/β-Catenin Signaling Pathway in Newborn Rat Lung

“…In newborn lung tissue, Wnt/βcatenin signaling pathway affects lung cell differentiation and lung tissue structure, and is abnormal activation in the lungs of rats with pulmonary fibrosis [10]. Wnt/β-catenin pathway was activated in lung tissue in animal models of BPD and idiopathic pulmonary fibrosis, which suggested that Wnt/β-catenin pathway had potential as a therapeutic target for the treatment and prevention of BPD [11,12].…”