Fibrosis is an impairment of normal tissue maintenance resulting in scar-like deposits that disrupt tissue structure and function. A growing body of evidence shows that the presence of senescent cells can cause the fibrosis that is characteristic of age-related dysfunction in organs such as the heart, lungs, and kidneys. Of particular interest are the animal studies of recent years demonstrating that clearance of senescent cells can reverse fibrosis. There is no medical technology presently in widespread clinical use that can reliable and significantly reverse fibrosis, and thus some of the first human trials for senolytic therapies capable of selectively destroying senescent cells are targeting fibrotic diseases of the lung and kidney.
Despite the good evidence linking senescent cells to the development of fibrosis in aging organs, the specific molecular mechanisms by which inflammatory senescent cell signaling causes fibrosis remain unclear. In the open access paper noted here, researchers report on progress towards a better understanding in the matter of lung fibrosis. The specific mechanisms implicated are already known to be involved in heart fibrosis as well, so it may be the case that there is just the one link between cellular senescence and fibrosis that applies to all tissues.
Fibrosis is a shared pathological characteristic of many fatal lung diseases, such as idiopathic pulmonary fibrosis (IPF), which exhibits epithelial cell senescence and abundant foci of highly activated pulmonary fibroblasts. To date, there is no effective cure for these fibrotic diseases, as there is an incomplete understanding of the pathogenesis. In the progression of IPF, epithelial cell senescence has been demonstrated to occur in IPF and experimental lung fibrosis models. 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 the senescence-associated secretory phenotype (SASP). Cell-cell contact between epithelial cells and fibroblasts appears to be essential in signalling cascades and important for wound repair. Pulmonary fibroblasts co-cultured with senescent epithelial cells expressed higher levels of collagen I, vimentin, and α-SMA, suggesting that senescent epithelial cells could effectively induce the activation of pulmonary fibroblasts.
We found that 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. Thus the 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.