Progenitor identification and SARS-CoV-2 infection in human distal lung organoids
The distal lung contains terminal bronchioles and alveoli that facilitate gas exchange. Three-dimensional in vitro human distal lung culture systems would strongly facilitate the investigation of pathologies such as interstitial lung disease, cancer and coronavirus disease 2019 (COVID-19) pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here we describe the development of a long-term feeder-free, chemically defined culture system for distal lung progenitors as organoids derived from single adult human alveolar epithelial type II (AT2) or KRT5+ basal cells. AT2 organoids were able to differentiate into AT1 cells, and basal cell organoids developed lumens lined with differentiated club and ciliated cells. Single-cell analysis of KRT5+ cells in basal organoids revealed a distinct population of ITGA6+ITGB4+ mitotic cells, whose offspring further segregated into a TNFRSF12Ahi subfraction that comprised about ten per cent of KRT5+ basal cells. This subpopulation formed clusters within terminal bronchioles and exhibited enriched clonogenic organoid growth activity. We created distal lung organoids with apical-out polarity to present ACE2 on the exposed external surface, facilitating infection of AT2 and basal cultures with SARS-CoV-2 and identifying club cells as a target population. This long-term, feeder-free culture of human distal lung organoids, coupled with single-cell analysis, identifies functional heterogeneity among basal cells and establishes a facile in vitro organoid model of human distal lung infections, including COVID-19-associated pneumonia.
| Errataetall: | |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:588 |
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| Enthalten in: |
Nature - 588(2020), 7839 vom: 26. Dez., Seite 670-675 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Salahudeen, Ameen A [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 06.01.2021 Date Revised 09.04.2024 published: Print-Electronic UpdateOf: bioRxiv. 2020 Jul 27;:. - PMID 32743583 Citation Status MEDLINE |
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| doi: |
10.1038/s41586-020-3014-1 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM318049171 |
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| 100 | 1 | |a Salahudeen, Ameen A |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Progenitor identification and SARS-CoV-2 infection in human distal lung organoids |
| 264 | 1 | |c 2020 | |
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| 500 | |a Date Completed 06.01.2021 | ||
| 500 | |a Date Revised 09.04.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a UpdateOf: bioRxiv. 2020 Jul 27;:. - PMID 32743583 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a The distal lung contains terminal bronchioles and alveoli that facilitate gas exchange. Three-dimensional in vitro human distal lung culture systems would strongly facilitate the investigation of pathologies such as interstitial lung disease, cancer and coronavirus disease 2019 (COVID-19) pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here we describe the development of a long-term feeder-free, chemically defined culture system for distal lung progenitors as organoids derived from single adult human alveolar epithelial type II (AT2) or KRT5+ basal cells. AT2 organoids were able to differentiate into AT1 cells, and basal cell organoids developed lumens lined with differentiated club and ciliated cells. Single-cell analysis of KRT5+ cells in basal organoids revealed a distinct population of ITGA6+ITGB4+ mitotic cells, whose offspring further segregated into a TNFRSF12Ahi subfraction that comprised about ten per cent of KRT5+ basal cells. This subpopulation formed clusters within terminal bronchioles and exhibited enriched clonogenic organoid growth activity. We created distal lung organoids with apical-out polarity to present ACE2 on the exposed external surface, facilitating infection of AT2 and basal cultures with SARS-CoV-2 and identifying club cells as a target population. This long-term, feeder-free culture of human distal lung organoids, coupled with single-cell analysis, identifies functional heterogeneity among basal cells and establishes a facile in vitro organoid model of human distal lung infections, including COVID-19-associated pneumonia | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a ITGA6 protein, human |2 NLM | |
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| 700 | 1 | |a Choi, Shannon S |e verfasserin |4 aut | |
| 700 | 1 | |a Rustagi, Arjun |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Junjie |e verfasserin |4 aut | |
| 700 | 1 | |a van Unen, Vincent |e verfasserin |4 aut | |
| 700 | 1 | |a de la O, Sean M |e verfasserin |4 aut | |
| 700 | 1 | |a Flynn, Ryan A |e verfasserin |4 aut | |
| 700 | 1 | |a Margalef-Català, Mar |e verfasserin |4 aut | |
| 700 | 1 | |a Santos, António J M |e verfasserin |4 aut | |
| 700 | 1 | |a Ju, Jihang |e verfasserin |4 aut | |
| 700 | 1 | |a Batish, Arpit |e verfasserin |4 aut | |
| 700 | 1 | |a Usui, Tatsuya |e verfasserin |4 aut | |
| 700 | 1 | |a Zheng, Grace X Y |e verfasserin |4 aut | |
| 700 | 1 | |a Edwards, Caitlin E |e verfasserin |4 aut | |
| 700 | 1 | |a Wagar, Lisa E |e verfasserin |4 aut | |
| 700 | 1 | |a Luca, Vincent |e verfasserin |4 aut | |
| 700 | 1 | |a Anchang, Benedict |e verfasserin |4 aut | |
| 700 | 1 | |a Nagendran, Monica |e verfasserin |4 aut | |
| 700 | 1 | |a Nguyen, Khanh |e verfasserin |4 aut | |
| 700 | 1 | |a Hart, Daniel J |e verfasserin |4 aut | |
| 700 | 1 | |a Terry, Jessica M |e verfasserin |4 aut | |
| 700 | 1 | |a Belgrader, Phillip |e verfasserin |4 aut | |
| 700 | 1 | |a Ziraldo, Solongo B |e verfasserin |4 aut | |
| 700 | 1 | |a Mikkelsen, Tarjei S |e verfasserin |4 aut | |
| 700 | 1 | |a Harbury, Pehr B |e verfasserin |4 aut | |
| 700 | 1 | |a Glenn, Jeffrey S |e verfasserin |4 aut | |
| 700 | 1 | |a Garcia, K Christopher |e verfasserin |4 aut | |
| 700 | 1 | |a Davis, Mark M |e verfasserin |4 aut | |
| 700 | 1 | |a Baric, Ralph S |e verfasserin |4 aut | |
| 700 | 1 | |a Sabatti, Chiara |e verfasserin |4 aut | |
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| 700 | 1 | |a Desai, Tushar J |e verfasserin |4 aut | |
| 700 | 1 | |a Kuo, Calvin J |e verfasserin |4 aut | |
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