Transcriptome analysis indicates more AT2-to-AT1 transition in COPD

Background: Alveolar type 2 (AT2) cells, as progenitors of alveolar type 1 (AT1) cells, play a central role in alveolar repair in chronic obstructive pulmonary disease (COPD). We aimed to explore potential mechanisms of impaired alveolar repair in COPD at the transcriptomic level. Methods: We isolated EpCAM⁺ cells from lung tissue of 10 COPD patients and 9 controls. Total RNA from these cells was analyzed by sequencing. Cellular deconvolution based on cell type-specific gene expression was used to estimate cell type composition. Differential gene expression was assessed by linear models. Enrichment analysis was done using hypergeometric distribution. Results: Both AT1 and AT2 cell proportions were similar comparing COPD and controls, and AT2 cells were the main component of isolated EpCAM⁺ cells. We found that 7 genes with roles in cell cycle were higher, and 15 genes with roles in differentiation, energy metabolism, complement system and tumor suppression were lower in the AT2 expression profile of COPD (FDR<0.05). Regarding AT1 and AT2 markers, lower expression of surfactant genes and quiescent AT2 markers CA2 and HHIP, and higher expression of the signaling AT2 marker TCF4 and AT2-to-AT1 transitional markers KRT8/KRT18 were found in COPD, whereas no differences were observed in AT1 markers (P<0.05). Enrichment analysis showed that surfactant and lipid metabolism pathways were inhibited, while mRNA\RNA\DNA splicing and transcription pathways were activated in COPD. Conclusions: Our results suggest enhanced AT2 cell proliferation and differentiation in COPD. Upregulation of the AT2-to-AT1 transitional markers suggests these cells remain in the intermediate state, which may contribute to hampered alveolar repair.