Lung epithelial-endothelial-mesenchymal signaling network with hepatocyte growth factor as a hub is involved in bronchopulmonary dysplasia

Abstract

Bronchopulmonary dysplasia (BPD) is fundamentally characterized by the arrest of lung development and abnormal repair mechanisms, which result in impaired development of the alveoli and microvasculature. Hepatocyte growth factor (HGF), secreted by pulmonary mesenchymal and endothelial cells, plays a pivotal role in the promotion of epithelial and endothelial cell proliferation, branching morphogenesis, angiogenesis, and alveolarization. HGF exerts its beneficial effects on pulmonary vascular development and alveolar simplification primarily through two pivotal pathways: the stimulation of neovascularization, thereby enriching the pulmonary microvascular network, and the inhibition of the epithelial-mesenchymal transition (EMT), which is crucial for maintaining the integrity of the alveolar structure. We discuss HGF and its receptor c-Met, interact with various growth factors throughout the process of lung development and BPD, and form a signaling network with HGF as a hub, which plays the pivotal role in orchestrating and integrating epithelial, endothelial and mesenchymal.

Keywords: angiogenesis; bronchopulmonary dysplasia (BPD); epithelial-mesenchymal transition (EMT); growth factors; hepatocyte growth factor (HGF).

FIGURE 1

Hepatocyte Growth Factor (HGF) Signaling Pathway in Alveolar Epithelial cells (AECs) and Endothelial Cells (ECs) in Lung Development. HGF, partly secreted by ECs, through paracrine and autocrine mechanisms, binds to the c-Met receptor on AECs and ECs. This interaction triggers a cascade of downstream signaling molecules that primarily promote cell proliferation and anti-apoptotic effects. Additionally, HGF regulates cytoskeletal dynamics, cellular migration, and morphogenesis by activating Rho and FAK (By Figdraw).

FIGURE 2

The Role of HGF in the Crosstalk between Lung Mesenchyme-Endothelium-Epithelium. HGF, derived from endothelial cells, activates the Rap1 signaling pathway, recruiting myofibroblasts (MYF) and promoting the deposition of extracellular matrix (ECM) proteins, including elastin and collagen. Increased ECM stiffness, through mechanosignaling, leads to the dephosphorylation and activation of YAP/TAZ, thereby stimulating the secretion of HGF by myofibroblasts (MYFs). Hyperoxia upregulates the expression of TGFβ, which promotes epithelial-mesenchymal transition (EMT) in epithelial cells. HGF inhibits the occurrence of EMT by antagonizing the expression of TGFβ and degrading ECM-related proteins (By Figdraw).