TRPC6 mediates goblet cell differentiation in COPD.

backgroundGoblet cell metaplasia is a pathological feature of airway remodelling in chronic obstructive pulmonary disease (COPD). Basal cell clones with goblet cell metaplasia demonstrate high transient receptor potential cation channel subfamily C member 6 (TRPC6) expression, but its biological function remains unclear.

methodsTRPC6 expression was analysed by immunostaining in lung tissues and airway basal cells from patients with COPD, and in the airways of mice exposed to cigarette smoke or interleukin-13. In vitro, the role of TRPC6 was assessed by TRPC6 overexpression and depletion in air–liquid interface cultures of human bronchial epithelial cells. In vivo, TRPC6 function was tested by airway TRPC6 depletion and TRPC6 inhibition in mice exposed to interleukin-13. NOTCH signalling was confirmed as a downstream pathway of TRPC6 by performing rescue experiments.

resultsTRPC6 expression was increased in the airway epithelium of patients with COPD and in interleukin-13-exposed mice. TRPC6 overexpression in basal cells from patients without COPD promoted their differentiation into goblet cells, while TRPC6 depletion in basal cells from patients with COPD suppressed goblet cell metaplasia in air–liquid interface cultures. TRPC6 function in suppressed goblet cell metaplasia was confirmed in TRPC6 depletion mice and TRPC6 inhibitor-treated mice. NOTCH signalling increased in interleukin-13-exposed control mice and human bronchial epithelial cell air–liquid interface cultures and decreased after TRPC6 inhibition.

conclusionsTRPC6 regulated basal cell differentiation, underscoring its potential as a therapeutic target in COPD. The in vivo experiments used mice exposed to interleukin-13, so its clinical potential requires clarification.