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

The role of the chronic obstructive pulmonary disease (COPD) susceptibility gene hedgehog (Hh) interacting protein (<i>HHIP</i>) 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 trophic unit. HHIP expression was assessed in lung tissue and airway epithelial cells (AECs) from patients with COPD and non-COPD controls. The effect of HHIP overexpression was assessed on cigarette smoke extract (CSE)-induced changes in epithelial plasticity genes, for example, cadherin 1 (<i>CDH1</i>, encoding E-cadherin) in human bronchial epithelial cells (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 the lung tissue of patients with COPD, whereas the expression of <i>HHIP</i> was significantly lower in COPD-derived AECs compared with the control. HHIP overexpression in 16HBE cells attenuated the CSE-induced reduction in <i>CDH1</i> expression. Furthermore, overexpression of HHIP significantly suppressed Sonic hedgehog-induced <i>GLI1</i> expression in control but not COPD-derived LMSCs and resulted in the 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 <i>FGF10</i> upon HHIP overexpression in COPD compared with 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.<b>NEW & NOTEWORTHY</b> We show that overexpression of HHIP protected from cigarette smoke-induced epithelial-to-mesenchymal transition and promoted epithelial regeneration via epithelial-mesenchymal cross talk in non-COPD controls. Thus, the lower expression of HHIP in airway epithelial cells from patients with COPD may contribute to abnormal epithelial repair in both proximal and distal parts of the lungs of patients with COPD.