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Glypican-3 is a key tuner of the Hedgehog pathway in COPD
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International audience. Hedgehog (HH) pathway is involved in pulmonary development and lung homeostasis. It orchestrates 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 patientswith chronic obstructive pulmonary disease (COPD). Here, we investigated the co-receptors tofully decipher the complex machinery of airway HH pathway activation in health and COPD. Thecore elements and co-receptors of HH signalling were investigated in lung cell populations usingsingle-cell RNAseq analysis. The transcript levels of the principal co-receptor GPC3 were investigated on public RNAseq datasets and by RT-qPCR. The localisation of GPC3 was evaluatedthrough immunofluorescent stainings on isolated bronchial AEC and tissues from non-COPD andCOPD patients. GPC3 pharmacological modulation was achieved with Codrituzumab during AECdifferentiation. We demonstrated that the core elements were not abundant in pulmonary cellpopulations. Focusing on co-receptors, GPC3 was the most expressed transcript in tracheobronchial epithelial cells. The decrease in GPC3 transcript levels correlated with the severity of airwayobstrution in COPD patients. Finally, interfering with GPC3 signalling during AEC differentiationinduced downregulation of the HH pathway attested by a decrease of Gli2 leading to reducedciliogenesis and altered mucin production. GPC3 appears as a crucial co-receptor for the HHpathway in the respiratory context. The modulation of GPC3 may represent a novel experimentalstrategy to tune HH signalling in therapeutic perspectives.
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