Downregulation of MCM2 contributes to the reduced growth potential of epithelial progenitor cells in chronic nasal inflammation

Abstract Background Recent studies have shown that human nasal epithelial progenitor cells (hNEPCs) are characterized by poor proliferation capacities during chronic nasal inflammation. Objective We sought to investigate the key molecular functions and candidates that contribute to the reduced growth potential of hNEPCs in chronically inflamed nasal mucosa. Methods Nasal biopsies were obtained from 28 patients with nasal polyps (NP) and 13 healthy controls. hNEPCs from nasal samples were cultured for three consecutive passages and their molecular/functional profiles were analysed by RNA sequencing. The minichromosome maintenance protein (MCM) family gene MCM2 was validated in hNEPCs and tissues from NP patients and control subjects by cell cycle, quantitative PCR, and western blot analyses; siRNA-mediated knockdown assay; and immunofluorescent staining. Results Compared with control hNEPCs, NP-derived hNEPCs showed 1) reduced growth kinetics, as evidenced by the colony-forming efficiency and doubling time; 2) inhibited cell cycle progression, as evidenced by gene ontology/pathway and cell cycle analyses; and 3) downregulated expression of MCM2, the key protein of the MCM complex that is critical for DNA replication at the G1/S checkpoint. Moreover, hNEPCs with MCM2 knockdown showed a decreased proliferation rate, and the MCM2 protein level in basal cells was significantly lower in abnormally remodelled nasal epithelium than in normal epithelium. Conclusion These results demonstrate inhibited cell cycle progression and MCM2 downregulation in basal or progenitor nasal epithelial cells from NP tissues, whichmay contribute to the decreased growth potential of hNEPCs in chronically inflamed upper airways.