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

Sandra Ruiz Garcia, Marie Deprez, View ORCID ProfileKevin Lebrigand, View ORCID ProfileAgnès Paquet, Amélie Cavard, Marie-Jeanne Arguel, Virginie Magnone, Ignacio Caballero, View ORCID ProfileSylvie Leroy, View ORCID ProfileCharles-Hugo Marquette, View ORCID ProfileBrice Marcet, View ORCID ProfilePascal Barbry, View ORCID ProfileLaure-Emmanuelle Zaragosi
doi: https://doi.org/10.1101/451807
Sandra Ruiz Garcia
1Université Côte d’Azur, CNRS, IPMC, Sophia-Antipolis, France.
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Marie Deprez
1Université Côte d’Azur, CNRS, IPMC, Sophia-Antipolis, France.
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Kevin Lebrigand
1Université Côte d’Azur, CNRS, IPMC, Sophia-Antipolis, France.
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Agnès Paquet
1Université Côte d’Azur, CNRS, IPMC, Sophia-Antipolis, France.
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Amélie Cavard
1Université Côte d’Azur, CNRS, IPMC, Sophia-Antipolis, France.
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Marie-Jeanne Arguel
1Université Côte d’Azur, CNRS, IPMC, Sophia-Antipolis, France.
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Virginie Magnone
1Université Côte d’Azur, CNRS, IPMC, Sophia-Antipolis, France.
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Ignacio Caballero
2ISP, INRA, Université Tours, 37380, Nouzilly, France.
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Sylvie Leroy
1Université Côte d’Azur, CNRS, IPMC, Sophia-Antipolis, France.
3Université Côte d’Azur, CHU de Nice, Pulmonology Department, Nice, France.
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Charles-Hugo Marquette
3Université Côte d’Azur, CHU de Nice, Pulmonology Department, Nice, France.
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Brice Marcet
1Université Côte d’Azur, CNRS, IPMC, Sophia-Antipolis, France.
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Pascal Barbry
1Université Côte d’Azur, CNRS, IPMC, Sophia-Antipolis, France.
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Laure-Emmanuelle Zaragosi
1Université Côte d’Azur, CNRS, IPMC, Sophia-Antipolis, France.
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Abstract

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.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted October 24, 2018.
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Single-cell RNA sequencing reveals novel cell differentiation dynamics during human airway epithelium regeneration
Sandra Ruiz Garcia, Marie Deprez, Kevin Lebrigand, Agnès Paquet, Amélie Cavard, Marie-Jeanne Arguel, Virginie Magnone, Ignacio Caballero, Sylvie Leroy, Charles-Hugo Marquette, Brice Marcet, Pascal Barbry, Laure-Emmanuelle Zaragosi
bioRxiv 451807; doi: https://doi.org/10.1101/451807
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Single-cell RNA sequencing reveals novel cell differentiation dynamics during human airway epithelium regeneration
Sandra Ruiz Garcia, Marie Deprez, Kevin Lebrigand, Agnès Paquet, Amélie Cavard, Marie-Jeanne Arguel, Virginie Magnone, Ignacio Caballero, Sylvie Leroy, Charles-Hugo Marquette, Brice Marcet, Pascal Barbry, Laure-Emmanuelle Zaragosi
bioRxiv 451807; doi: https://doi.org/10.1101/451807

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