Epithelial cell senescence induces pulmonary fibrosis through Nanog-mediated fibroblast activation.

Hui Wang,Yi Zheng,Xiaodong Han,Hui Li,Hourong Cai,Jinghong Dai,Hongyang Xu,Xiang Chen,Jiwei Hou

doi:10.18632/aging.102613

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease tightly correlated with aging. The pathological features of IPF include epithelial cell senescence and abundant foci of highly activated pulmonary fibroblasts. However, the underlying mechanism between epithelial cell senescence and pulmonary fibroblast activation remain to be elucidated. In our study, we demonstrated that Nanog, as a pluripotency gene, played an essential role in the activation of pulmonary fibroblasts. In the progression of IPF, senescent epithelial cells could contribute to the activation of pulmonary fibroblasts via increasing the expression of senescence-associated secretory phenotype (SASP). In addition, we found activated pulmonary fibroblasts exhibited aberrant activation of Wnt/β-catenin signalling and elevated expression of Nanog. Further study revealed that the activation of Wnt/β-catenin signalling was responsible for senescent epithelial cell-induced Nanog phenotype in pulmonary fibroblasts. β-catenin was observed to bind to the promoter of Nanog during the activation of pulmonary fibroblasts. Targeted inhibition of epithelial cell senescence or Nanog could effectively suppress the activation of pulmonary fibroblasts and impair the development of pulmonary fibrosis, indicating a potential for the exploration of novel anti-fibrotic strategies.

Highlights

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease, which is characterized with fibroblastic proliferation, cystically remodelled air spaces and irregular scars composed of dense collagen fibrosis [1, 2]
The results showed an increased expression of established senescence markers in the lung tissues derived from IPF (Figure 1A and 1B)
We found that increased positive staining of SA-β-gal and p16 were located in the epithelial area (Figure 1C, black arrow), which was hardly seen in normal lung tissues

Summary

Introduction

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease, which is characterized with fibroblastic proliferation, cystically remodelled air spaces and irregular scars composed of dense collagen fibrosis [1, 2]. Increasing evidence has demonstrated an accumulation of senescent cells in IPF lung tissues, which were primarily in the epithelium and less frequently in fibroblasts [7, 8]. These senescent epithelial cells covering fibroblastic foci were found in IPF lungs, while they were not present in normal lungs [9]. Senescent cells could secrete increased amounts of interleukin (IL), including IL-1β, IL-6 and IL-8, which could induce the differentiation of fibroblasts into myofibroblasts [9] These findings indicated that senescence may exacerbate the pathogenesis of IPF through promoting the abnormal secretory pattern of the lung epithelium and enhancing the resistance of myofibroblasts to apoptosis

Methods

Results

Conclusion