Sox21 modulates sox2-initiated differentiation of epithelial cells in the extrapulmonary airways

Evelien Eenjes; Marjon Buscop-Van Kempen; Anne Boerema-De Munck; Gabriela G. Edel; Erasmus University Benthem; Lisette de Kreij-De Bruin; J. Marco Schnater; Dick Tibboel; Jennifer J.P. Collins; Robbert J. Rottier

doi:10.7554/eLife.57325

Sox21 modulates sox2-initiated differentiation of epithelial cells in the extrapulmonary airways

Evelien Eenjes, Marjon Buscop-Van Kempen, Anne Boerema-De Munck, Gabriela G. Edel, Erasmus University Benthem, Lisette de Kreij-De Bruin, J. Marco Schnater, Dick Tibboel, Jennifer J.P. Collins, Robbert J. Rottier^*

^*Corresponding author for this work

Neonatal and Pediatric Intensive Care

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

SOX2 expression levels are crucial for the balance between maintenance and differentiation of airway progenitor cells during development and regeneration. Here, we describe patterning of the mouse proximal airway epithelium by SOX21, which coincides with high levels of SOX2 during development. Airway progenitor cells in this SOX2+/SOX21+ zone show differentiation to basal cells, specifying cells for the extrapulmonary airways. Loss of SOX21 showed an increased differentiation of SOX2+ progenitor cells to basal and ciliated cells during mouse lung development. We propose a mechanism where SOX21 inhibits differentiation of airway progenitors by antagonizing SOX2-induced expression of specific genes involved in airway differentiation. Additionally, in the adult tracheal epithelium SOX21 inhibits basal to ciliated cell differentiation. This suppressing function of SOX21 on differentiation contrasts SOX2, which mainly drives differentiation of epithelial cells during development and regeneration after injury. Furthermore, using human fetal lung organoids and adult bronchial epithelial cells, we show that SOX2+/SOX21+ regionalization is conserved. Lastly, we show that the interplay between SOX2 and SOX21 is context and concentration dependent leading to regulation of differentiation of the airway epithelium.

Original language	English
Article number	e57325
Journal	eLife
Volume	10
DOIs	https://doi.org/10.7554/eLife.57325
Publication status	Published - 21 Jul 2021

Bibliographical note

Funding Information:
We thank, Mart Lamers and Bart Haagmans (Department of Viroscience, Erasmus MC) for assistance and supplying the human fetal lung organoids, Thomas Koudstaal (department of Pulmonary Medicine, Erasmus MC) for supplying lung resection material for the isolation of human primary bronchial epithelial cells, Rutger Brouwer (Department of Biomics, Erasmus MC) for Figure 7-supplement 6H and Frank Grosveld for critically reading the manuscript (Department of Cell Biology, Erasmus MC). This work was supported by a grant from the Sophia Foundation for Medical Research (grant number S14-12 EE; S17-20 GGE).

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© 2021, eLife Sciences Publications Ltd. All rights reserved.

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SOX21 modulates SOX2-initiated differentiation of epithelial cells in the extrapulmonary airwaysFinal published version, 11.5 MBLicence: CC BY

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@article{52fb752f538940c38bca9429c4561665,

title = "Sox21 modulates sox2-initiated differentiation of epithelial cells in the extrapulmonary airways",

abstract = "SOX2 expression levels are crucial for the balance between maintenance and differentiation of airway progenitor cells during development and regeneration. Here, we describe patterning of the mouse proximal airway epithelium by SOX21, which coincides with high levels of SOX2 during development. Airway progenitor cells in this SOX2+/SOX21+ zone show differentiation to basal cells, specifying cells for the extrapulmonary airways. Loss of SOX21 showed an increased differentiation of SOX2+ progenitor cells to basal and ciliated cells during mouse lung development. We propose a mechanism where SOX21 inhibits differentiation of airway progenitors by antagonizing SOX2-induced expression of specific genes involved in airway differentiation. Additionally, in the adult tracheal epithelium SOX21 inhibits basal to ciliated cell differentiation. This suppressing function of SOX21 on differentiation contrasts SOX2, which mainly drives differentiation of epithelial cells during development and regeneration after injury. Furthermore, using human fetal lung organoids and adult bronchial epithelial cells, we show that SOX2+/SOX21+ regionalization is conserved. Lastly, we show that the interplay between SOX2 and SOX21 is context and concentration dependent leading to regulation of differentiation of the airway epithelium.",

author = "Evelien Eenjes and \{Buscop-Van Kempen\}, Marjon and \{Boerema-De Munck\}, Anne and Edel, \{Gabriela G.\} and Benthem, \{Erasmus University\} and \{de Kreij-De Bruin\}, Lisette and Schnater, \{J. Marco\} and Dick Tibboel and Collins, \{Jennifer J.P.\} and Rottier, \{Robbert J.\}",

note = "Funding Information: We thank, Mart Lamers and Bart Haagmans (Department of Viroscience, Erasmus MC) for assistance and supplying the human fetal lung organoids, Thomas Koudstaal (department of Pulmonary Medicine, Erasmus MC) for supplying lung resection material for the isolation of human primary bronchial epithelial cells, Rutger Brouwer (Department of Biomics, Erasmus MC) for Figure 7-supplement 6H and Frank Grosveld for critically reading the manuscript (Department of Cell Biology, Erasmus MC). This work was supported by a grant from the Sophia Foundation for Medical Research (grant number S14-12 EE; S17-20 GGE). Publisher Copyright: {\textcopyright} 2021, eLife Sciences Publications Ltd. All rights reserved.",

year = "2021",

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doi = "10.7554/eLife.57325",

language = "English",

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T1 - Sox21 modulates sox2-initiated differentiation of epithelial cells in the extrapulmonary airways

AU - Eenjes, Evelien

AU - Buscop-Van Kempen, Marjon

AU - Boerema-De Munck, Anne

AU - Edel, Gabriela G.

AU - Benthem, Erasmus University

AU - de Kreij-De Bruin, Lisette

AU - Schnater, J. Marco

AU - Tibboel, Dick

AU - Collins, Jennifer J.P.

AU - Rottier, Robbert J.

N1 - Funding Information: We thank, Mart Lamers and Bart Haagmans (Department of Viroscience, Erasmus MC) for assistance and supplying the human fetal lung organoids, Thomas Koudstaal (department of Pulmonary Medicine, Erasmus MC) for supplying lung resection material for the isolation of human primary bronchial epithelial cells, Rutger Brouwer (Department of Biomics, Erasmus MC) for Figure 7-supplement 6H and Frank Grosveld for critically reading the manuscript (Department of Cell Biology, Erasmus MC). This work was supported by a grant from the Sophia Foundation for Medical Research (grant number S14-12 EE; S17-20 GGE). Publisher Copyright: © 2021, eLife Sciences Publications Ltd. All rights reserved.

PY - 2021/7/21

Y1 - 2021/7/21

N2 - SOX2 expression levels are crucial for the balance between maintenance and differentiation of airway progenitor cells during development and regeneration. Here, we describe patterning of the mouse proximal airway epithelium by SOX21, which coincides with high levels of SOX2 during development. Airway progenitor cells in this SOX2+/SOX21+ zone show differentiation to basal cells, specifying cells for the extrapulmonary airways. Loss of SOX21 showed an increased differentiation of SOX2+ progenitor cells to basal and ciliated cells during mouse lung development. We propose a mechanism where SOX21 inhibits differentiation of airway progenitors by antagonizing SOX2-induced expression of specific genes involved in airway differentiation. Additionally, in the adult tracheal epithelium SOX21 inhibits basal to ciliated cell differentiation. This suppressing function of SOX21 on differentiation contrasts SOX2, which mainly drives differentiation of epithelial cells during development and regeneration after injury. Furthermore, using human fetal lung organoids and adult bronchial epithelial cells, we show that SOX2+/SOX21+ regionalization is conserved. Lastly, we show that the interplay between SOX2 and SOX21 is context and concentration dependent leading to regulation of differentiation of the airway epithelium.

AB - SOX2 expression levels are crucial for the balance between maintenance and differentiation of airway progenitor cells during development and regeneration. Here, we describe patterning of the mouse proximal airway epithelium by SOX21, which coincides with high levels of SOX2 during development. Airway progenitor cells in this SOX2+/SOX21+ zone show differentiation to basal cells, specifying cells for the extrapulmonary airways. Loss of SOX21 showed an increased differentiation of SOX2+ progenitor cells to basal and ciliated cells during mouse lung development. We propose a mechanism where SOX21 inhibits differentiation of airway progenitors by antagonizing SOX2-induced expression of specific genes involved in airway differentiation. Additionally, in the adult tracheal epithelium SOX21 inhibits basal to ciliated cell differentiation. This suppressing function of SOX21 on differentiation contrasts SOX2, which mainly drives differentiation of epithelial cells during development and regeneration after injury. Furthermore, using human fetal lung organoids and adult bronchial epithelial cells, we show that SOX2+/SOX21+ regionalization is conserved. Lastly, we show that the interplay between SOX2 and SOX21 is context and concentration dependent leading to regulation of differentiation of the airway epithelium.

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Sox21 modulates sox2-initiated differentiation of epithelial cells in the extrapulmonary airways

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