Regulation of Human Airway Epithelial Tissue Stem Cell Differentiation by β-Catenin, P300, and CBP.
Publication/Presentation Date
12-1-2018
Abstract
The wingless/integrase-1 (WNT)/β-catenin signaling pathway is active in several chronic lung diseases including idiopathic pulmonary fibrosis, asthma, and chronic obstructive pulmonary disease. Although this WNT/β-catenin pathway activity is associated with an increase in mucus cell frequency and a decrease in ciliated cell frequency, a cause and consequence relationship between signaling and cell frequency has not been established. We previously demonstrated that genetic stabilization of β-catenin inhibited differentiation of mouse bronchiolar tissue stem cells (TSC). This study determined the effect of β-catenin and its co-factors P300 (E1A-binding protein, 300 kDa) and cAMP response element binding (CREB)-binding protein (CBP) on human bronchial epithelial TSC differentiation to mucus and ciliated cells. We developed a modified air-liquid interface (ALI) culture system in which mucus and ciliated cell frequency is similar. These cultures were treated with the β-catenin agonist CHIR99021 (CHIR) and antagonists to β-catenin (XAV939), P300 (IQ1), and CBP (ICG001). We report that human TSC differentiation to mucus and ciliated cells can be divided into two stages, specification and commitment. CHIR treatment inhibited mucus and ciliated cell commitment while XAV939 treatment demonstrated that β-catenin was necessary for mucus and ciliated cell specification. Additional studies demonstrate that a β-catenin/P300 complex promotes mucus cell specification and that β-catenin interacts with either P300 or CBP to inhibit ciliated cell commitment. These data indicate that activation of β-catenin-dependent signaling in chronic lung disease leads to changes in mucus and ciliated cell frequency and that P300 and CBP tune the β-catenin signal to favor mucus cell differentiation. Stem Cells 2018;36:1905-12.
Volume
36
Issue
12
First Page
1905
Last Page
1916
ISSN
1549-4918
Published In/Presented At
Malleske, D. T., Hayes, D., Jr, Lallier, S. W., Hill, C. L., & Reynolds, S. D. (2018). Regulation of Human Airway Epithelial Tissue Stem Cell Differentiation by β-Catenin, P300, and CBP. Stem cells (Dayton, Ohio), 36(12), 1905–1916. https://doi.org/10.1002/stem.2906
Disciplines
Medicine and Health Sciences | Pediatrics
PubMedID
30171668
Department(s)
Department of Pediatrics
Document Type
Article
