The Hedgehog System Machinery Controls Transforming Growth Factor-β–Dependent Myofibroblastic Differentiation in Humans

Abstract

Idiopathic pulmonary fibrosis (IPF) is a devastating disease of unknown cause. Key signaling developmental pathways are aberrantly expressed in IPF. The hedgehog pathway plays a key role during fetal lung development and may be involved in lung fibrogenesis. We determined the expression pattern of several Sonic hedgehog (SHH) pathway members in normal and IPF human lung biopsies and primary fibroblasts. The effect of hedgehog pathway inhibition was assayed by lung fibroblast proliferation and differentiation with and without transforming growth factor (TGF)-β1. We showed that the hedgehog pathway was reactivated in the IPF lung. Importantly, we deciphered the cross talk between the hedgehog and TGF-β pathway in human lung fibroblasts. TGF-β1 modulated the expression of key components of the hedgehog pathway independent of Smoothened, the obligatory signal transducer of the pathway. Smoothened was required for TGF-β1-induced myofibroblastic differentiation of control fibroblasts, but differentiation of IPF fibroblasts was partially resistant to Smoothened inhibition. Furthermore, functional hedgehog pathway machinery from the primary cilium, as well as GLI-dependent transcription in the nucleus, was required for the TGF-β1 effects on normal and IPF fibroblasts during myofibroblastic differentiation. These data identify the GLI transcription factors as potential therapeutic targets in lung fibrosis.

Tissue remodelling in chronic bronchial diseases: from the epithelial to mesenchymal phenotype

“…Moreover, in fibroblasts, Shh increases the synthesis of proteins related to ECM, such as collagen and fibronectin [112,113]. Interestingly, inhibition of the Hh pathway reduces the expression of a-SMA, collagen 1 and fibronectin and abrogates the effect of TGF-b on these proteins [111], highlighting the importance of the TGF-b/Hh crosstalk that may promote a mesenchymal phenotype in pathological contexts. In different types of lung cancer, the Shh pathway has also been found to be re-activated [99,[113][114][115][116], and is involved in the mesenchymal transition of tumoural cells associated with the formation of metastases.…”

“…In the lung, expression of the Shh ligand is increased in patients with usual interstitial pneumonia, nonspecific interstitial pneumonia [109], cryptogenic pneumonia [110] or IPF [111,112]. Recent studies in IPF lungs have revealed distinct expression of Hh-related proteins in IPF tissues [111,112]. Shh is expressed in bronchial and alveolar epithelial cells in fibrotic areas while Ptch1 is observed in fibroblasts, interstitial inflammatory cells and the hyperplastic epithelium.…”

“…Furthermore, in Ptch+/-mice, the over-activation of the Hh pathway parallels an increase in EMT and an aggravated liver fibrosis [108]. In the lung, expression of the Shh ligand is increased in patients with usual interstitial pneumonia, nonspecific interstitial pneumonia [109], cryptogenic pneumonia [110] or IPF [111,112]. Recent studies in IPF lungs have revealed distinct expression of Hh-related proteins in IPF tissues [111,112].…”

“…The impact of Shh in cell migration can also be due to the interaction between this pathway and other signalling cascades such as TGF-b, one of the main factors involved in EMT. Evidence has shown an interaction between the Shh and TGF-b Smad pathway during development, but also in adult tissues [111,[120][121][122]. This type of interaction can enhance EMT effects in bronchial chronic lung diseases.…”

Sonic hedgehog signaling in kidney fibrosis: a master communicator

“…In adult kidneys, however, Shh expression is largely silenced. Re-activation of Shh signaling has been implicated in the pathogenesis of tissue fibrosis in many organs including kidney, lung and liver (Chung et al, 2016; Cigna et al, 2012; Zhou et al, 2014). …”