TGF-alpha/EGFR signalling mediates retinoic acid-induced lung repair

Lung repair involves coordination of multicellular processes, including endothelial angiogenesis and epithelial repopulation. Retinoic acid (RA) signalling is crucial for lung development, homeostasis, and repair, however, the mechanisms through which RA drives repair are still unknown. It has previously been shown that RA has no direct effects on repair of alveolar epithelium, yet in animal studies, RA induces alveolar regeneration. Here we show that RA-induces endothelial angiogenesis which elicits paracrine effects on alveolar epithelial cells to drive repair. Transcriptomic profiling of RA-treated HPMECs undergoing angiogenesis revealed enrichment of wound healing pathways and subsequent in-silico analysis identified several secreted factors as potential mediators of paracrine pro-repair effects on the epithelium. Scratch assays demonstrated that of these secreted factors, only TGFα promoted wound healing in alveolar epithelial A549 and primary human alveolar type 2 (hAT2) cells. Further investigation determined that TGFα promoted epithelial repair by enhancing cell migration through EGFR activation, without affecting proliferation or apoptosis. Our findings identify the TGFα/EGFR axis as a key mediator of RA-induced alveolar repair and provide a potential novel therapeutic avenue to enhance alveolar regeneration.