Nestin promotes pulmonary fibrosisviafacilitating recycling of TGF-β receptor I

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease that is characterised by aberrant proliferation of activated myofibroblasts and pathological remodelling of the extracellular matrix. Previous studies have revealed that the intermediate filament protein Nestin plays key roles in tissue regeneration and wound healing in different organs. Whether Nestin plays a critical role in the pathogenesis of IPF needs to be clarified.Nestin expression in lung tissues from bleomycin-treated mice and IPF patients was determined. Transfection with Nestin shRNA vectors in vitro that regulated TGF-β/Smad signalling was conducted. Biotinylation assays to observe plasma membrane TβRI, TβRI endocytosis and TβRI recycling after Nestin knockdown were performed. Adeno-associated virus serotype 6 (AAV6)-mediated Nestin knockdown was assessed in vivo.We found that Nestin expression was increased in a murine pulmonary fibrosis model and IPF patients, and that the upregulated protein primarily localised in lung α-SMA+ myofibroblasts. Mechanistically, we determined that Nestin knockdown inhibited TGF-β signalling by suppressing recycling of TβRI to the cell surface and that Rab11 was required for the ability of Nestin to promote TβRI recycling. In vivo, we found that intratracheal administration of adeno-associated virus serotype 6 (AAV6)-mediated Nestin knockdown significantly alleviated pulmonary fibrosis in multiple experimental mice models.In conclusion, our findings reveal a pro-fibrotic function of Nestin partially through facilitating Rab11-dependent recycling of TβRI and shed new light on pulmonary fibrosis treatment.

Immune Mechanisms of Pulmonary Fibrosis with Bleomycin

“…Previous studies have reported that the intermediate filament protein nestin plays an important role in tissue regeneration and wound healing in various organs [ 285 , 286 ]. Wang et al found that nestin expression was primarily localized to lung myofibroblasts and increased in a mouse model of pulmonary fibrosis and in patients with IPF [ 287 ]. The deficiency of nestin significantly alleviated pulmonary fibrosis in a mouse model.…”

Nestin-dependent mitochondria-ER contacts define stem Leydig cell differentiation to attenuate male reproductive ageing

“…In addition, in order to further illustrate the functional significance of Nestin in MERCs, we used two Nestin-short hairpin RNAs (ShNES-1 or ShNES-2) as previously reported to specifically reduce Nestin expression in SLCs 33 , 34 (Supplementary Fig. 7a–c ).…”

“…For loss of Nestin function, retrovirus vectors (pSM2) encoding Nestin shRNA were used according to previous articles 33 , 34 . Scramble shRNA was used as a control.…”

Photobiomodulation therapy enhances neural differentiation of dental pulp stem cells via ERK1/2 signaling pathway

“…It is an intermediate filament protein expressed in NSCs. 34 Also, NCAM is a cell surface glycoprotein capable of mediating cell adhesion and neurite formation. 35 The present study showed that irradiation could significantly promote the expression of neural differentiation-related genes in neuroshperes derived from DPSCs.…”