Distinct Spatiotemporally Dynamic Wnt-Secreting Niches Regulate Proximal Airway Regeneration and Aging

Aros, Cody J.; Vijayaraj, Preethi; Pantoja, Carla J; Bisht, Bharti; Meneses, Luisa K.; Sandlin, Jenna M.; Tse, Jonathan A.; Chen, Michelle W.; Purkayastha, Arunima; Shia, David W.; Sucre, Jennifer M. S.; Rickabaugh, Tammy M.; Vladar, Eszter K.; Paul, Manash K.; Gomperts, Brigitte N.

doi:10.1016/j.stem.2020.06.019

Cited by 38 publications

(25 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Once the micro-environment balance is disrupted, AEC senescence is initiated [ 34 ]. Cross-talk, such as that among IGF1, TGF-β, and Wnt, can also induce AECs senescence [ 35 – 37 ]. Blockade of a single signaling pathway can inhibit IPF to some extent; however, other pathways would be activated in compensation.…”

Section: Discussionmentioning

confidence: 99%

Regulation of the IGF1 signaling pathway is involved in idiopathic pulmonary fibrosis induced by alveolar epithelial cell senescence and core fucosylation

Sun

Jing

Yang

et al. 2021

Aging

View full text Add to dashboard Cite

Idiopathic pulmonary fibrosis (IPF) mainly occurs in elderly people over the age of sixty. IPF pathogenesis is associated with alveolar epithelial cells (AECs) senescence. Activation of PI3K/AKT signaling induced by insulin-like growth factor 1 (IGF1) participates in AEC senescence and IPF by releasing CTGF, TGF-β1, and MMP9. Our previous study demonstrated that core fucosylation (CF) modification, catalyzed by a specific core fucosyltransferase (FUT8) can regulate the activation of multiple signaling pathways, and inhibiting CF can alleviate pulmonary fibrosis in mice induced by bleomycin. However, whether CF is involved in IGF1-mediated AEC senescence in IPF remains unclear. In this study, we found that the IGF1/PI3K/AKT signaling pathway was activated in IPF lung tissue. Meanwhile, CF was present in senescent AECs. We also showed that IGF1 could induce AECs senescence with enhanced CF in vivo and in vitro . Inhibiting CF alleviated AECs senescence and pulmonary fibrosis induced by IGF1. In addition, activation of IGF1/PI3K/AKT signaling depends on CF. In conclusion, this study confirmed that CF is an important target regulating the IGF1 signaling pathway in AEC senescence and IPF, which might be a candidate target to treat IPF in the future.

show abstract

Section: Discussionmentioning

confidence: 99%

Regulation of the IGF1 signaling pathway is involved in idiopathic pulmonary fibrosis induced by alveolar epithelial cell senescence and core fucosylation

Sun

Jing

Yang

et al. 2021

Aging

View full text Add to dashboard Cite

show abstract

“…In addition, as described above, Wnt signals facilitate MEC contribution to proximal airway regeneration following severe injury 48 . At the cellular level, a recent group identified that a subset of Pdgfrα+ cells in the intercartilaginous zone are transiently, dynamically activated to secrete Wnt ligand that signals to the airway epithelium to promote its proliferation 64 . During differentiation, β-catenin activity is increased in air–liquid interface (ALI) cultures, a culturing system used to model airway epithelial remodeling, and enhances specification for the ciliated cell lineage 61 .…”

Section: Proximal Airway Homeostasis and Regenerationmentioning

confidence: 99%

“…During differentiation, β-catenin activity is increased in air–liquid interface (ALI) cultures, a culturing system used to model airway epithelial remodeling, and enhances specification for the ciliated cell lineage 61 . In vivo, this phase is also driven by Wnt secretion from K5+ ABSCs that are necessary for differentiation to the ciliated cell fate 64 .…”

Section: Proximal Airway Homeostasis and Regenerationmentioning

confidence: 99%

“…In particular, we need to better dissect the spatiotemporal relationship between the diverse cell types of the airway as it relates to Wnt signaling. Previous work has illustrated the critical importance of mesenchymal-epithelial cell crosstalk for mediating airway regeneration 64 , 89 . As such, these efforts should be expanded to the realm of Wnt/β-catenin signaling given its appreciated importance.…”

Section: Distal Lung Homeostasis and Regenerationmentioning

confidence: 99%

See 1 more Smart Citation

Wnt signaling in lung development, regeneration, and disease progression

2021

Self Cite

View full text Add to dashboard Cite

The respiratory tract is a vital, intricate system for several important biological processes including mucociliary clearance, airway conductance, and gas exchange. The Wnt signaling pathway plays several crucial and indispensable roles across lung biology in multiple contexts. This review highlights the progress made in characterizing the role of Wnt signaling across several disciplines in lung biology, including development, homeostasis, regeneration following injury, in vitro directed differentiation efforts, and disease progression. We further note uncharted directions in the field that may illuminate important biology. The discoveries made collectively advance our understanding of Wnt signaling in lung biology and have the potential to inform therapeutic advancements for lung diseases.

show abstract

“…While mesenchymal cells (e.g., fibroblasts) are the major regulators of ECM deposition and organization, our data suggest that NOTCH3 signaling may have a similar role in regulating airway epithelial-derived ECM production. Similar to NOTCH signaling, Wnt/β-catenin signaling also plays a crucial role in regulating cell fate decisions in the human lung [52,[62][63][64][65][66][67]. Therefore, our data demonstrating NOTCH3 activation modulates expression of multiple genes in the Wnt/β-catenin signaling pathway suggest that NOTCH3 may cross-talk with this pathway to regulate airway epithelial differentiation.…”

Section: Discussionmentioning

confidence: 66%

The NOTCH3 Downstream Target HEYL Is Required for Efficient Human Airway Basal Cell Differentiation

Bodas

Bharathiraja

Moore

et al. 2021

Cells

View full text Add to dashboard Cite

Basal cells (BCs) are stem/progenitor cells of the mucociliary airway epithelium, and their differentiation is orchestrated by the NOTCH signaling pathway. NOTCH3 receptor signaling regulates BC to club cell differentiation; however, the downstream responses that regulate this process are unknown. Overexpression of the active NOTCH3 intracellular domain (NICD3) in primary human bronchial epithelial cells (HBECs) on in vitro air–liquid interface culture promoted club cell differentiation. Bulk RNA-seq analysis identified 692 NICD3-responsive genes, including the classical NOTCH target HEYL, which increased in response to NICD3 and positively correlated with SCGB1A1 (club cell marker) expression. siRNA knockdown of HEYL decreased tight junction formation and cell proliferation. Further, HEYL knockdown reduced club, goblet and ciliated cell differentiation. In addition, we observed decreased expression of HEYL in HBECs from donors with chronic obstructive pulmonary disease (COPD) vs. normal donors which correlates with the impaired differentiation capacity of COPD cells. Finally, overexpression of HEYL in COPD HBECs promoted differentiation into club, goblet and ciliated cells, suggesting the impaired capacity of COPD cells to generate a normal airway epithelium is a reversible phenotype that can be regulated by HEYL. Overall, our data identify the NOTCH3 downstream target HEYL as a key regulator of airway epithelial differentiation.

show abstract

Distinct Spatiotemporally Dynamic Wnt-Secreting Niches Regulate Proximal Airway Regeneration and Aging

Cited by 38 publications

References 65 publications

Regulation of the IGF1 signaling pathway is involved in idiopathic pulmonary fibrosis induced by alveolar epithelial cell senescence and core fucosylation

Regulation of the IGF1 signaling pathway is involved in idiopathic pulmonary fibrosis induced by alveolar epithelial cell senescence and core fucosylation

Wnt signaling in lung development, regeneration, and disease progression

The NOTCH3 Downstream Target HEYL Is Required for Efficient Human Airway Basal Cell Differentiation

Contact Info

Product

Resources

About