Understanding the regenerative capacity and the role of human AT2s in the distal lung is imperative for defining alveolar response to injury and disease. Additionally, due to human AT2 expression of COPD genome wide association study (GWAS) genes, they are an especially relevant cell type to study the disease. Here we apply CRISPR-interference (CRISPRi) to reduce the expression of COPD GWAS gene, ADGRG6, to interrogate its function in induced pluripotent stem cell-derived type 2 alveolar epithelial cells (iAT2s). We find that decreased expression of ADGRG6 in iAT2s caused disruption to iAT2 cell polarity, organization of the actin cytoskeleton, and establishment of tight junctions. In addition, ADGRG6 knockdown (kd) causes a hyperproliferative phenotype. Finally, we find that ADGRG6-kd may contribute to dysregulation of tight junction formation in the presence of cigarette smoke.