Alteration in the Wnt microenvironment directly regulates molecular events leading to pulmonary senescence

Abstract

In the aging lung, the lung capacity decreases even in the absence of diseases. The progenitor cells of the distal lung, the alveolar type II cells (ATII), are essential for the repair of the gas-exchange surface. Surfactant protein production and survival of ATII cells are supported by lipofibroblasts that are peroxisome proliferator-activated receptor gamma (PPARγ)-dependent special cell type of the pulmonary tissue. PPARγ levels are directly regulated by Wnt molecules; therefore, changes in the Wnt microenvironment have close control over maintenance of the distal lung. The pulmonary aging process is associated with airspace enlargement, decrease in the distal epithelial cell compartment and infiltration of inflammatory cells. qRT–PCR analysis of purified epithelial and nonepithelial cells revealed that lipofibroblast differentiation marker parathyroid hormone-related protein receptor (PTHrPR) and PPARγ are reduced and that PPARγ reduction is regulated by Wnt4 via a β-catenin-dependent mechanism. Using a human in vitro 3D lung tissue model, a link was established between increased PPARγ and pro-surfactant protein C (pro-SPC) expression in pulmonary epithelial cells. In the senile lung, both Wnt4 and Wnt5a levels increase and both Wnt-s increase myofibroblast-like differentiation. Alteration of the Wnt microenvironment plays a significant role in pulmonary aging. Diminished lipo- and increased myofibroblast-like differentiation are directly regulated by specific Wnt-s, which process also controls surfactant production and pulmonary repair mechanisms.

Syndecan-1 promotes lung fibrosis by regulating epithelial reprogramming through extracellular vesicles

“…Furthermore, recent studies using scRNA-Seq approaches have reinforced the importance of aberrant Wnt activation in the ATII cells within the fibrotic lungs (48,50). Wnt/β-catenin signaling is dysregulated in the aged lung and promotes senescence, and a pathogenic feature of reprogrammed fibrotic lung epithelial cells is cellular senescence (8,9,48,60,61). Altogether, these findings suggest that aberrant signaling through this pathway can promote lung fibrosis via initiation of cellular senescence.…”

ABCB1 and ABCG2 drug transporters are differentially expressed in non-small cell lung cancers (NSCLC) and expression is modified by cisplatin treatment via altered Wnt signaling

“…Aggregates containing NHLF, SAEC and HMVEC-L cells were mixed at 4:3:3 ratio, and dispensed onto poly-HEMA-coated (final concentration 20 mg/ml) 96-well plates (TPP, Sigma-Aldrich, St. Louis, USA) as described earlier [28]. The plates were centrifuged for 10 min at 600 x g at 4°C.…”

Increased Wnt5a in squamous cell lung carcinoma inhibits endothelial cell motility

“…As only the beta-catenin dependent canonical Wnt signaling has been reported repeatedly to down-regulate PPARs [30, 44] and consequently up-regulate VEGF-A [47], it was not clear how SCC samples with high levels of non-canonical Wnt ligands (Fig. 3a and b) can trigger the same mechanism?…”

“…For better understanding of the process of PPARgamma down-regulation we considered that down-regulation of PPARgamma transcription is a beta-catenin-dependent and therefore canonical Wnt pathway dependent process [44]. As lung ACs are characterized by increased canonical and therefore beta-catenin dependent Wnt signal activity [58] such molecular basis can explain PPARgamma reduction in AC [44].…”

“…As lung ACs are characterized by increased canonical and therefore beta-catenin dependent Wnt signal activity [58] such molecular basis can explain PPARgamma reduction in AC [44]. The similarly high VEGF-A and reduced PPARgamma levels in SCC samples seem counter-intuitive as in SCC the non-canonical, beta-catenin independent Wnts play the dominant role [59].…”