COPD susceptibility gene HHIP regulates repair genes in airway epithelial cells and repair within the epithelial-mesenchymal trophic unit.

Abstract

The role of COPD susceptibility gene Hedgehog (Hh) Interacting Protein (HHIP) in lung tissue damage and abnormal repair in COPD is incompletely understood. We hypothesized that dysregulated HHIP expression affects cigarette smoke-induced epithelial damage and repair within the epithelial-mesenchymal tropic unit. HHIP expression was assessed in lung tissue and airway epithelial cells (AECs) from COPD patients and non-COPD controls. The effect of HHIP overexpression was assessed on cigarette smoke extract (CSE)-induced changes in epithelial plasticity genes, e.g. Cadherin 1 (CDH1, encoding E-cadherin) in 16HBE cells, and on epithelial-mesenchymal interactions during alveolar repair as modeled by organoid formation using distal lung-derived mesenchymal stromal cells (LMSCs) and EpCAM⁺ epithelial cells. We observed no abnormalities in HHIP protein levels in lung tissue of COPD patients, while the expression of HHIP was significantly lower in COPD-derived AECs compared to control. HHIP overexpression in 16HBE cells attenuated the CSE-induced reduction in CDH1 expression. Furthermore, overexpression of HHIP significantly suppressed Sonic hedgehog-induced GLI1 expression in control but not COPD-derived LMSCs, and resulted in formation of more and larger organoids, which was not observed for COPD-derived LMSCs. This defect was accompanied by lower expression of the growth factor FGF10 upon HHIP overexpression in COPD compared to control-derived LMSCs. Together, our data suggest a protective role of HHIP in CSE-induced airway epithelial responses and a supportive role in alveolar epithelial regeneration, which may be impaired in COPD.