Mesenchymal WNT-5A/5B Signaling Represses Lung Alveolar Epithelial Progenitors

Abstract

Chronic obstructive pulmonary disease (COPD) represents a worldwide concern with high morbidity and mortality, and is believed to be associated with accelerated ageing of the lung. Alveolar abnormalities leading to emphysema are a key characteristic of COPD. Pulmonary alveolar epithelial type 2 cells (AT2) produce surfactant and function as progenitors for type 1 cells. Increasing evidence shows elevated WNT-5A/B expression in ageing and in COPD that may contribute to the disease process. However, supportive roles for WNT-5A/B in lung regeneration were also reported in different studies. Thus, we explored the role of WNT-5A/B on alveolar epithelial progenitors (AEPs) in more detail. We established a Precision-Cut-Lung Slices (PCLS) model and a lung organoid model by co-culturing epithelial cells (EpCAM+/CD45-/CD31-) with fibroblasts in matrigel in vitro to study the impact of WNT-5A and WNT-5B. Our results show that WNT-5A and WNT-5B repress the growth of epithelial progenitors with WNT-5B preferentially restraining the growth and differentiation of alveolar epithelial progenitors. We provide evidence that both WNT-5A and WNT-5B negatively regulate the canonical WNT signaling pathway in alveolar epithelium. Taken together, these findings reveal the functional impact of WNT-5A/5B signaling on alveolar epithelial progenitors in the lung, which may contribute to defective alveolar repair in COPD.

Distinct populations of crypt-associated fibroblasts act as signaling hubs to control colon homeostasis

“…Taken together with the expression of Bmp ligands (e.g., Bmp2 and Bmp4) and marker gene F3, the data suggest that the colonic CTFs are likely analogous to the villus tip telocytes observed in the small intestine [22]. Wnt5a has been show to inhibit canonical Wnt signaling by down-regulating transcription of Wnt target genes [34,35], which is consistent with the proposed role of CTFs in orchestrating epithelial differentiation. Upon intestinal injury, Wnt5a is required for the proper subdivision of wound channels and thereby the formation of new crypts [36].…”

The Planar Polarity Component VANGL2 Is a Key Regulator of Mechanosignaling

“…It is also notable that several independent datasets from emphysema patients, in which repair capacity is diminished, show significant downregulation of VANGL2 and WNT5A (Ezzie et al, 2012;Poobalasingam et al, 2017;Zhang et al, 2020). However, contradictory findings with regard to pro-repair/migratory (Witze et al, 2008;Vuga et al, 2009;Gao et al, 2011;Poobalasingam et al, 2017;Yuan et al, 2019;Li et al, 2020;Zhang et al, 2020) or anti-repair effects (Baarsma et al, 2017;Wu et al, 2019;Sucre et al, 2020) of WNT5A suggest that the complex mechanism of action of WNT5A may be cell type or tissue context-dependent or may differ depending on the balance between PCP and other signaling pathways, such as canonical Wnt signaling. Thus, it will be important to carry out further detailed investigation of how WNT5A stimulates repair in Vangl2 Lp/+ mice.…”

Canonical WNT pathway is activated in the airway epithelium in chronic obstructive pulmonary disease

“…WNT pathways have been studied in COPD where persistent reactivation of developmental pathways – such as WNT, Notch, Sonic hedgehog, as well as TGF-β – emerged as a new paradigm [18] . Previous studies showed that upregulated noncanonical WNT signalling, through increased WNT-5a and −5b [ 19 , 20 ], contributes to emphysema (characterized by the disruption of alveolar walls) by negatively regulating alveolar repair, while decreased FZD4 in COPD leads to reduced canonical signalling and impaired alveolar repair capacity [21] . On the other hand, extrinsic activation of the canonical pathway (by LiCl or CHIR99021) in elastase-induced murine emphysema [22] and ex-vivo three-dimensional murine lung tissue cultures [23] attenuated those COPD features at the alveolar level.…”