Regulation of Human Airway Epithelial Tissue Stem Cell Differentiation by β-Catenin, P300, and CBP

Malleske, Daniel T.; Hayes, Don; Lallier, Scott W.; Hill, Cynthia L.; Reynolds, Susan D.

doi:10.1002/stem.2906

Cited by 35 publications

(52 citation statements)

References 47 publications

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“…Wnt/β-catenin signaling functions in mucociliary epithelia, but results from manipulations often appear contradictory as to the exact roles Wnt signaling plays in different cell types and processes. Wnt/β-catenin was suggested to promote MCC specification and expression of FOXJ1 , a key transcription factor in motile cilia formation (Hou et al, 2019; Huang and Niehrs, 2014; Malleske et al, 2018; Stubbs et al, 2008; Walentek et al, 2012, 2015). In contrast, Wnt/β-catenin activation can also lead to loss of MCCs or Goblet secretory cell hyperplasia (Hashimoto et al, 2012; Mucenski et al, 2005; Reynolds et al, 2008; Schmid et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

ΔN-Tp63 mediates Wnt/β-catenin-induced inhibition of differentiation in basal stem cells of mucociliary epithelia

Haas

Vázquez

Sun

et al. 2019

Preprint

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SummaryMucociliary epithelia provide a first line of defense against pathogens in the airways and the epidermis of vertebrate larvae. Impaired regeneration and remodeling of mucociliary epithelia are associated with dysregulated Wnt/β-catenin signaling in chronic airway diseases, but underlying mechanisms remain elusive and studies of Wnt signaling in mucociliary cells yield seemingly contradicting results. Employing the Xenopus mucociliary epidermis, the mouse airway, and human airway basal stem cell cultures, we characterize the evolutionarily conserved roles of Wnt/β-catenin signaling in mucociliary cells in vertebrates. Wnt signaling is required in multiciliated cells for cilia formation during differentiation stages, but in Basal cells, Wnt signaling prevents specification and differentiation of epithelial cell types by activating ΔN-TP63 expression. We demonstrate that ΔN-TP63 is a master transcription factor in Basal cells, which is necessary and sufficient to mediate the Wnt-induced inhibition of differentiation and is required to retain basal stem cells during development. Chronic stimulation of Wnt signaling leads to mucociliary remodeling and Basal cell hyperplasia, but this is reversible in vivo and in vitro, suggesting Wnt inhibition as an option in the treatment of chronic lung diseases. Our work sheds light into the evolutionarily conserved regulation of stem cells and differentiation, resolves Wnt functions in mucociliary epithelia, and provides crucial insights into mucociliary development, regeneration and disease mechanisms.

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Section: Introductionmentioning

confidence: 99%

ΔN-Tp63 mediates Wnt/β-catenin-induced inhibition of differentiation in basal stem cells of mucociliary epithelia

Haas

Vázquez

Sun

et al. 2019

Preprint

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“…In MCCs, we have observed a specific expression of both members from the Reptin family which are ATP-dependent DNA helicases that have been identified as Wnt signaling repressors [63,64]. As Reynolds and colleagues recently showed that β-catenin was necessary for mucus and ciliated cell specification [57], additional investigations should certainly be carried out to characterize precisely the role of Wnt/β-catenin during airway epithelial regeneration.…”

Section: Discussionmentioning

confidence: 86%

“…For instance, in the hair follicle precortex, βcatenin stimulates Notch signaling by inducing Jag1 transcription [56]. In the context of airway epithelium, a very recent study demonstrated that β-catenin signaling is required for the early stages of mucus and ciliated cell differentiation, which they defined as "specification", but was detrimental to the later "commitment" stages [57]. Wnt also seems to be related to epithelial remodeling upon inflammatory situations: Ordovas-Montanes and colleagues have recently shown that in nasal polyps, which are characterized by an inflammatory state favoring GCs at the expense of MCCs, there is an altered balance between Wnt and Notch signaling, in favor of Wnt signaling [30].…”

Section: Discussionmentioning

confidence: 99%

Single-cell RNA sequencing reveals novel cell differentiation dynamics during human airway epithelium regeneration

García-Ruiz

Deprez

Lebrigand

et al. 2018

Preprint

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Background:It is usually considered that the upper airway epithelium is composed of multiciliated, goblet, secretory and basal cells, which collectively constitute an efficient first line of defense against inhalation of noxious substances. Upon injury, regeneration of this epithelium through proliferation and differentiation can restore a proper mucociliary function. However, in chronic airway diseases, the injured epithelium frequently displays defective repair leading to tissue remodeling, characterized by a loss of multiciliated cells and mucus hyper-secretion. Delineating drivers of differentiation dynamics and cell fate in the human airway epithelium is important to preserve homeostasis. Results:We have used single cell transcriptomics to characterize the sequence of cellular and molecular processes taking place during human airway epithelium regeneration. We have characterized airway subpopulations with high resolution and lineage inference algorithms have unraveled cell trajectories from basal to luminal cells, providing markers for specific cell populations, such as deuterosomal cells, i.e. precursors of multiciliated cells. We report that goblet cells, like secretory cells, can act as precursors of multiciliated cells. Our study provides a repertoire of molecules involved in key steps of the regeneration process, either keratins or components of the Notch, Wnt or BMP/TGFβ signaling pathways. Our findings were confirmed in independent experiments performed on fresh human and pig airway samples, and on mouse tracheal epithelial cells. Conclusions:Our single-cell RNA-seq study provides novel insights about airway epithelium differentiation dynamics, clarifies cell trajectories between secretory, goblet and multiciliated cells, identifies novel cell subpopulations, and maps the activation and repression of key signaling pathways.

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“…Prior studies unveiled that b-catenin is dispensable in the bronchiolar airways for homeostasis and injury repair (Zemke et al, 2009), while others affirmed that it may play a role in specification of mucus and ciliated cells in vitro (Malleske et al, 2018). In the proximal airway, we find that medium levels of Wnt/b-catenin signaling promote differentiation to the ciliated cell fate, consistent with work of others that has molecularly dissected a role for Wnt/ b-catenin in regulating Foxj1-driven ciliogenesis across several species (Caron et al, 2012;Walentek et al, 2012Walentek et al, , 2015.…”

Section: Discussionmentioning

confidence: 99%

High-Throughput Drug Screening Identifies a Potent Wnt Inhibitor that Promotes Airway Basal Stem Cell Homeostasis

et al. 2020

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Graphical Abstract Highlights d A dysregulated Wnt/b-catenin axis in human lung premalignancy can be modeled in vitro d High-throughput drug screening identifies the Wnt/b-catenin inhibitor WIC1 d Low-dose treatment with WIC1 promotes differentiation to the ciliated cell fate d WIC1 acts to repress phosphorylation of b-catenin Y489 and Tp63 expression SUMMARYMechanisms underpinning airway epithelial homeostatic maintenance and ways to prevent its dysregulation remain elusive. Herein, we identify that b-catenin phosphorylated at Y489 (p-b-catenin Y489 ) emerges during human squamous lung cancer progression. This led us to develop a model of airway basal stem cell (ABSC) hyperproliferation by driving Wnt/b-catenin signaling, resulting in a morphology that resembles premalignant lesions and loss of ciliated cell differentiation. To identify small molecules that could reverse this process, we performed a high-throughput drug screen for inhibitors of Wnt/ b-catenin signaling. Our studies unveil Wnt inhibitor compound 1 (WIC1), which suppresses T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) activity, reduces ABSC proliferation, induces ciliated cell differentiation, and decreases nuclear p-b-catenin Y489 . Collectively, our work elucidates a dysregulated Wnt/p-b-catenin Y489 axis in lung premalignancy that can be modeled in vitro and identifies a Wnt/ b-catenin inhibitor that promotes airway homeostasis. WIC1 may therefore serve as a tool compound in regenerative medicine studies with implications for restoring normal airway homeostasis after injury.

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Regulation of Human Airway Epithelial Tissue Stem Cell Differentiation by β-Catenin, P300, and CBP

Cited by 35 publications

References 47 publications

ΔN-Tp63 mediates Wnt/β-catenin-induced inhibition of differentiation in basal stem cells of mucociliary epithelia

ΔN-Tp63 mediates Wnt/β-catenin-induced inhibition of differentiation in basal stem cells of mucociliary epithelia

Single-cell RNA sequencing reveals novel cell differentiation dynamics during human airway epithelium regeneration

High-Throughput Drug Screening Identifies a Potent Wnt Inhibitor that Promotes Airway Basal Stem Cell Homeostasis

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