Glypican-3 is a key tuner of the Hedgehog pathway in COPD
Résumé
Hedgehog (HH) pathway is involved in pulmonary development and lung homeostasis. It or
chestrates airway epithelial cell (AEC) differentiation and contributes to respiratory pathogenesis.
The core elements Gli2, Smo, and Shh were found altered in the bronchial epithelium of patients
with chronic obstructive pulmonary disease (COPD). Here, we investigated the co-receptors to
fully decipher the complex machinery of airway HH pathway activation in health and COPD. The
core elements and co-receptors of HH signalling were investigated in lung cell populations using
single-cell RNAseq analysis. The transcript levels of the principal co-receptor GPC3 were inves
tigated on public RNAseq datasets and by RT-qPCR. The localisation of GPC3 was evaluated
through immunofluorescent stainings on isolated bronchial AEC and tissues from non-COPD and
COPD patients. GPC3 pharmacological modulation was achieved with Codrituzumab during AEC
differentiation. We demonstrated that the core elements were not abundant in pulmonary cell
populations. Focusing on co-receptors, GPC3 was the most expressed transcript in tracheobron
chial epithelial cells. The decrease in GPC3 transcript levels correlated with the severity of airway
obstrution in COPD patients. Finally, interfering with GPC3 signalling during AEC differentiation
induced downregulation of the HH pathway attested by a decrease of Gli2 leading to reduced
ciliogenesis and altered mucin production. GPC3 appears as a crucial co-receptor for the HH
pathway in the respiratory context. The modulation of GPC3 may represent a novel experimental
strategy to tune HH signalling in therapeutic perspectives.
Domaines
Sciences du Vivant [q-bio]| Origine | Fichiers éditeurs autorisés sur une archive ouverte |
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