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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE168128 | GEO | 2021/03/04

REPOSITORIES: GEO

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

Project description: Not available

| S-EPMC8620267 | biostudies-literature

The NOTCH3 Downstream Target HEYL Is Required for Efficient Human Airway Basal Cell Differentiation [scRNA-Seq]

Project description:Basal cells (BC) are the resident stem/progenitor cells of the adult pseudostratified airway epithelium, whose differentiation program is orchestrated by the NOTCH signaling pathway. NOTCH3 receptor mediated signaling regulates BC to club cell differentiation; however, the downstream responses that regulate this process are largely unknown. In the present study we utilized an in vitro air-liquid interface model of the human pseudostratified airway epithelium to identify the NOTCH3-dependent downstream genes/pathways that regulate human BC to club cell differentiation. Activation of NOTCH3 signaling in BC via lentivirus-mediated over-expression of the active NOTCH3 intracellular domain (NICD3) promoted club cell differentiation. Bulk RNA-seq analysis of control vs NICD3 -transduced cells, identified 692 NICD3 responsive genes enriched for pathways linked to airway epithelial biology and differentiation including Wnt/β-catenin Signaling. Expression of the classical NOTCH target HEYL increased in response to NOTCH3 activation and positively correlated with the club cell marker SCGB1A1. Further, using single-cell RNA-seq, we report that HEYL+ cells primarily clustered with SCGB1A1+ and NOTCH3+ cells. Moreover, HEYL protein co-localized with SCGB1A1 in ALI cultures in vitro and in the human and mouse airway epithelium in vivo. siRNA-mediated knockdown of HEYL in BC led to changes in epithelial structure including altered morphology and significant reductions in transepithelial electrical resistance and expression of tight junction related genes. Finally, HEYL knockdown significantly reduced the number of SCGB1A1+ club cells, along with a corresponding increase in KRT8+ BC-intermediate cells. Overall, our data identifies NOTCH3-HEYL signaling as a key regulator of BC to club cell differentiation.

2021-03-04 | GSE168127 | GEO

The NOTCH3 Downstream Target HEYL Is Required for Efficient Human Airway Basal Cell Differentiation [RNA-Seq]

2021-03-04 | GSE168126 | GEO

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

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

| PRJNA706178 | ENA

The NOTCH3 Downstream Target HEYL Is Required for Efficient Human Airway Basal Cell Differentiation [RNA-Seq]

Project description:The NOTCH3 Downstream Target HEYL Is Required for Efficient Human Airway Basal Cell Differentiation [RNA-Seq]

| PRJNA706183 | ENA

The NOTCH3 Downstream Target HEYL Is Required for Efficient Human Airway Basal Cell Differentiation [scRNA-Seq]

Project description:The NOTCH3 Downstream Target HEYL Is Required for Efficient Human Airway Basal Cell Differentiation [scRNA-Seq]

| PRJNA706184 | ENA

Activation of NOTCH1 or NOTCH3 signaling skews human airway basal cell differentiation toward a secretory pathway.

Project description: Not available

| S-EPMC4336283 | biostudies-literature

Activation of Notch1 and Notch3 Skews Human Airway Basal Cell Differentiation Toward a Secretory Pathway

Project description:Airway basal cells (BC) function as progenitor cells capable of differentiating into ciliated and secretory cells to replenish the airway epithelium during physiological turnover and repair. The objective of this study was to define the role of Notch signaling in regulating human airway BC differentiation into a pseudostratified mucociliated epithelium. Notch inhibition with γ-secretase inhibitors demonstrated Notch activation is essential for BC differentiation into secre-tory cells and ciliated cells, but more so for the secretory lineage. Sustained Notch activation via lentivirus expression of the intracellular domain of each Notch receptor (NICD1-4) demonstrated that the Notch 2 and 4 pathways have little effect on BC differentiation, while activation of the Notch1 or 3 pathways has a major influence, with persistent expression of NICD1 or 3 resulting in a skewing toward secretory cell differentiation with a parallel decrease in ciliated cell differentiation. These observations provide insights into the control of the balance of BC differentiation into the secretory vs ciliated cell lineage, a balance that is critical for maintaining the normal function of the airway epithelium in barrier defense against the inhaled environment. Array-based expression profiling of the Notch signaling pathway genes specifically in human airway basal cells.

2015-04-13 | E-GEOD-53537 | biostudies-arrayexpress

Characterization of an Immortalized Human Small Airway Basal Stem/Progenitor Cell Line with Airway Region-specific Differentiation Capacity

Project description:This SuperSeries is composed of the SubSeries listed below.

2019-09-03 | GSE124265 | GEO

An inflammatory memory of COVID-19 in airway basal stem cells impairs mucociliary differentiation

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-06-01 | GSE212412 | GEO