EGF and EGFR Facilitate Alveolar Development by Promoting the Proliferation of Alveolar Type II Cells in the Yak (Bos grunniens)

Yaks (Bos grunniens) are large mammals endemic to the Qinghai–Tibet Plateau. Efficient lung development is crucial for their adaptation to high-altitude hypoxia. As progenitor cells of the alveoli, type II alveolar epithelial (AT2) cells warrant further investigation into their physiological functions; however, relevant studies remain limited. In this study, primary AT2 cells were isolated from the lungs of yaks. Concurrently, lung tissues were collected from yaks at distinct developmental stages to investigate the role of the EGF/EGFR axis in regulating AT2 cell proliferation and apoptosis, as well as its essential contribution to yak lung development. Here, we demonstrate that the EGF/EGFR axis plays a beneficial role in yak alveolar development. Exogenous EGF supplementation or EGFR activation upregulated the downstream factors AKT and STAT3, enhanced AT2 cell proliferation, and reduced apoptosis. In contrast, EGFR inhibition promoted AT2 cell apoptosis and suppressed proliferation. Cell cycle analysis revealed that both exogenous EGF and EGFR activation increased the proportion of AT2 cells in the S and G2 phases, whereas EGFR inhibition caused cell cycle arrest at the G0/G1 phase. Moreover, the expression of cell cycle regulators cyclin D1, CDK4, and CDK6 was upregulated, while p16 and p21 expression was downregulated. Further comparative analyses indicated that the EGF/EGFR axis positively contributes to alveolar development in juvenile yaks. Collectively, these findings confirm that in plateau environments, activation of the EGF/EGFR axis promotes AT2 cell proliferation and inhibits apoptosis, thereby facilitating alveolar development in juvenile yaks. A key limitation is the lack of parallel comparisons with low-altitude cattle and other plateau-endemic species (e.g., Tibetan sheep), which precludes definitive assessment of the specificity of the EGFR/EGF axis in yak AT2 cell proliferation and lung development.