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...

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Autores principales:	Manish Bodas, Bharathiraja Subramaniyan, Andrew R. Moore, Jordan P. Metcalf, Sarah R. Ocañas, Willard M. Freeman, Constantin Georgescu, Jonathan D. Wren, Matthew S. Walters
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	NOTCH3 signaling HEYL proliferation differentiation airway epithelium basal stem/progenitor cells Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/3eafc83ff2164f57934ce11e2e92f804
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spelling	oai:doaj.org-article:3eafc83ff2164f57934ce11e2e92f8042021-11-25T17:12:58ZThe NOTCH3 Downstream Target HEYL Is Required for Efficient Human Airway Basal Cell Differentiation10.3390/cells101132152073-4409https://doaj.org/article/3eafc83ff2164f57934ce11e2e92f8042021-11-01T00:00:00Zhttps://www.mdpi.com/2073-4409/10/11/3215https://doaj.org/toc/2073-4409Basal 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.Manish BodasBharathiraja SubramaniyanAndrew R. MooreJordan P. MetcalfSarah R. OcañasWillard M. FreemanConstantin GeorgescuJonathan D. WrenMatthew S. WaltersMDPI AGarticleNOTCH3 signalingHEYLproliferationdifferentiationairway epitheliumbasal stem/progenitor cellsBiology (General)QH301-705.5ENCells, Vol 10, Iss 3215, p 3215 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	NOTCH3 signaling HEYL proliferation differentiation airway epithelium basal stem/progenitor cells Biology (General) QH301-705.5
spellingShingle	NOTCH3 signaling HEYL proliferation differentiation airway epithelium basal stem/progenitor cells Biology (General) QH301-705.5 Manish Bodas Bharathiraja Subramaniyan Andrew R. Moore Jordan P. Metcalf Sarah R. Ocañas Willard M. Freeman Constantin Georgescu Jonathan D. Wren Matthew S. Walters The NOTCH3 Downstream Target HEYL Is Required for Efficient Human Airway Basal Cell Differentiation
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	article
author	Manish Bodas Bharathiraja Subramaniyan Andrew R. Moore Jordan P. Metcalf Sarah R. Ocañas Willard M. Freeman Constantin Georgescu Jonathan D. Wren Matthew S. Walters
author_facet	Manish Bodas Bharathiraja Subramaniyan Andrew R. Moore Jordan P. Metcalf Sarah R. Ocañas Willard M. Freeman Constantin Georgescu Jonathan D. Wren Matthew S. Walters
author_sort	Manish Bodas
title	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_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_sort	notch3 downstream target heyl is required for efficient human airway basal cell differentiation
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/3eafc83ff2164f57934ce11e2e92f804
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The NOTCH3 Downstream Target HEYL Is Required for Efficient Human Airway Basal Cell Differentiation

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