EGF/EGFR activation promotes yak AT2 cell proliferation and inhibits apoptosis, facilitating alveolar development

Efficient lung development is vital for adaptation to high-altitude hypoxia, a key challenge for species like the yak (Bos grunniens) on the Qinghai-Tibet Plateau. Alveolar type II (AT2) cells are critical progenitor cells for alveoli, yet their precise physiological regulation in such extreme environments remains understudied. Understanding the mechanisms governing AT2 cell proliferation and apoptosis is essential for addressing lung development challenges and potential therapeutic interventions in hypoxic conditions.

Researchers isolated primary AT2 cells from yak lungs and collected lung tissues from yaks at distinct developmental stages. They investigated the role of the EGF/EGFR axis by supplementing with exogenous EGF or activating/inhibiting EGFR in vitro. Key endpoints included AT2 cell proliferation, apoptosis, and cell cycle progression. Downstream signaling factors like AKT and STAT3 were assessed, alongside cell cycle regulators cyclin D1, CDK4, CDK6, p16, and p21 using methods like cell cycle analysis and expression profiling.

Activation of the EGF/EGFR axis demonstrated a beneficial role in yak alveolar development. Exogenous EGF supplementation or EGFR activation consistently upregulated downstream factors AKT and STAT3, leading to enhanced AT2 cell proliferation and reduced apoptosis. Conversely, EGFR inhibition promoted AT2 cell apoptosis and suppressed proliferation. Cell cycle analysis revealed that both exogenous EGF and EGFR activation significantly increased the proportion of AT2 cells in the S and G2 phases, while EGFR inhibition caused cell cycle arrest at the G0/G1 phase.

The expression of cell cycle regulators cyclin D1, CDK4, and CDK6 was upregulated, while p16 and p21 expression was downregulated, confirming a pro-proliferative effect. Comparative analyses further indicated that the EGF/EGFR axis positively contributes to alveolar development in juvenile yaks, suggesting its crucial role in high-altitude adaptation.