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The NOTCH3 Downstream Target HEYL Is Required for Efficient Human Airway Basal Cell Differentiation
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. O...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8620267/ https://www.ncbi.nlm.nih.gov/pubmed/34831437 http://dx.doi.org/10.3390/cells10113215 |
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author | Bodas, Manish Subramaniyan, Bharathiraja Moore, Andrew R. Metcalf, Jordan P. Ocañas, Sarah R. Freeman, Willard M. Georgescu, Constantin Wren, Jonathan D. Walters, Matthew S. |
author_facet | Bodas, Manish Subramaniyan, Bharathiraja Moore, Andrew R. Metcalf, Jordan P. Ocañas, Sarah R. Freeman, Willard M. Georgescu, Constantin Wren, Jonathan D. Walters, Matthew S. |
author_sort | Bodas, Manish |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8620267 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-86202672021-11-27 The NOTCH3 Downstream Target HEYL Is Required for Efficient Human Airway Basal Cell Differentiation Bodas, Manish Subramaniyan, Bharathiraja Moore, Andrew R. Metcalf, Jordan P. Ocañas, Sarah R. Freeman, Willard M. Georgescu, Constantin Wren, Jonathan D. Walters, Matthew S. Cells Article 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. MDPI 2021-11-18 /pmc/articles/PMC8620267/ /pubmed/34831437 http://dx.doi.org/10.3390/cells10113215 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Bodas, Manish Subramaniyan, Bharathiraja Moore, Andrew R. Metcalf, Jordan P. Ocañas, Sarah R. Freeman, Willard M. Georgescu, Constantin Wren, Jonathan D. Walters, Matthew S. The NOTCH3 Downstream Target HEYL Is Required for Efficient Human Airway Basal Cell Differentiation |
title | The NOTCH3 Downstream Target HEYL Is Required for Efficient Human Airway Basal Cell Differentiation |
title_full | The NOTCH3 Downstream Target HEYL Is Required for Efficient Human Airway Basal Cell Differentiation |
title_fullStr | The NOTCH3 Downstream Target HEYL Is Required for Efficient Human Airway Basal Cell Differentiation |
title_full_unstemmed | The NOTCH3 Downstream Target HEYL Is Required for Efficient Human Airway Basal Cell Differentiation |
title_short | The NOTCH3 Downstream Target HEYL Is Required for Efficient Human Airway Basal Cell Differentiation |
title_sort | notch3 downstream target heyl is required for efficient human airway basal cell differentiation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8620267/ https://www.ncbi.nlm.nih.gov/pubmed/34831437 http://dx.doi.org/10.3390/cells10113215 |
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