Emphysema and chronic obstructive pulmonary disease (COPD) most commonly result from the effects of environmental exposures in genetically susceptible individuals. Genome-wide association studies have implicated ADGRG6 in COPD and reduced lung function, and a limited number of studies have examined the role of ADGRG6 in cells representative of the airway. However, the ADGRG6 locus is also associated with DLCO/VA, an indicator of gas exchange efficiency and alveolar function. Here, we sought to evaluate the mechanistic contributions of ADGRG6 to homeostatic function and disease in type 2 alveolar epithelial cells. We applied an inducible CRISPR interference (CRISPRi) human induced pluripotent stem cell (iPSC) platform to explore ADGRG6 function in iPSC-derived AT2s (iAT2s). We demonstrate that ADGRG6 exerts pleiotropic effects on iAT2s including regulation of focal adhesions, cytoskeleton, tight junctions, and proliferation. Moreover, we find that ADGRG6 knockdown in cigarette smoke-exposed iAT2s alters cellular responses to injury, downregulating apical complexes in favor of proliferation. Our work functionally characterizes the COPD GWAS gene ADGRG6 in human alveolar epithelium.

肺气肿和慢性阻塞性肺病 (COPD) 最常见的原因是遗传易感个体的环境暴露影响。全基因组关联研究表明ADGRG6与 COPD 和肺功能下降有关，并且有限数量的研究检查了ADGRG6在代表气道的细胞中的作用。然而，ADGRG6基因座也与 DLCO/VA 相关，DLCO/VA 是气体交换效率和肺泡功能的指标。在这里，我们试图评估ADGRG6对 2 型肺泡上皮细胞稳态功能和疾病的机制贡献。我们应用诱导型 CRISPR 干扰 (CRISPRi) 人类诱导多能干细胞 (iPSC) 平台来探索iPSC 衍生的 AT2 (iAT2) 中的ADGRG6功能。我们证明ADGRG6对 iAT2 发挥多效性作用，包括调节粘着斑、细胞骨架、紧密连接和增殖。此外，我们发现暴露于香烟烟雾的 iAT2 中ADGRG6敲低会改变细胞对损伤的反应，下调顶端复合物有利于增殖。我们的工作从功能上表征了人类肺泡上皮中COPD GWAS 基因ADGRG6 。