A revised airway epithelial hierarchy includes CFTR-expressing ionocytes
Daniel T. Montoro,Adam L. Haber,Moshe Biton,Moshe Biton,Vladimir Vinarsky,Brian M. Lin,Susan E. Birket,Feng Yuan,Sijia Chen,Hui Min Leung,Jorge Villoria,Noga Rogel,Grace Burgin,Alexander M. Tsankov,Avinash Waghray,Michal Slyper,Julia Waldman,Lan Nguyen,Danielle Dionne,Orit Rozenblatt-Rosen,Purushothama Rao Tata,Hongmei Mou,Manjunatha Shivaraju,Hermann Bihler,Martin Mense,Guillermo J. Tearney,Steven M. Rowe,John F. Engelhardt,Aviv Regev,Aviv Regev,Jayaraj Rajagopal +30 more
TLDR
‘pulse-seq’ is developed, combining scRNA-seq and lineage tracing, to show that tuft, neuroendocrine and ionocyte cells are continually and directly replenished by basal progenitor cells, establishing a new cellular narrative for airways disease.Abstract:
The airways of the lung are the primary sites of disease in asthma and cystic fibrosis. Here we study the cellular composition and hierarchy of the mouse tracheal epithelium by single-cell RNA-sequencing (scRNA-seq) and in vivo lineage tracing. We identify a rare cell type, the Foxi1+ pulmonary ionocyte; functional variations in club cells based on their location; a distinct cell type in high turnover squamous epithelial structures that we term ‘hillocks’; and disease-relevant subsets of tuft and goblet cells. We developed ‘pulse-seq’, combining scRNA-seq and lineage tracing, to show that tuft, neuroendocrine and ionocyte cells are continually and directly replenished by basal progenitor cells. Ionocytes are the major source of transcripts of the cystic fibrosis transmembrane conductance regulator in both mouse (Cftr) and human (CFTR). Knockout of Foxi1 in mouse ionocytes causes loss of Cftr expression and disrupts airway fluid and mucus physiology, phenotypes that are characteristic of cystic fibrosis. By associating cell-type-specific expression programs with key disease genes, we establish a new cellular narrative for airways disease.read more
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SARS-CoV-2 Receptor ACE2 Is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Detected in Specific Cell Subsets across Tissues.
Carly G. K. Ziegler,Samuel J. Allon,Sarah K. Nyquist,Ian M. Mbano,Vincent N. Miao,Constantine N. Tzouanas,Yuming Cao,Ashraf S. Yousif,Julia Bals,Blake M. Hauser,Blake M. Hauser,Jared Feldman,Jared Feldman,Christoph Muus,Christoph Muus,Marc H. Wadsworth,Samuel W. Kazer,Travis K. Hughes,Benjamin Doran,G. James Gatter,G. James Gatter,G. James Gatter,Marko Vukovic,Faith Taliaferro,Faith Taliaferro,Benjamin E. Mead,Zhiru Guo,Jennifer P. Wang,Delphine Gras,Magali Plaisant,Meshal Ansari,Ilias Angelidis,Heiko Adler,Jennifer M.S. Sucre,Chase J. Taylor,Brian M. Lin,Avinash Waghray,Vanessa Mitsialis,Vanessa Mitsialis,Daniel F. Dwyer,Kathleen M. Buchheit,Joshua A. Boyce,Nora A. Barrett,Tanya M. Laidlaw,Shaina L. Carroll,Lucrezia Colonna,Victor Tkachev,Victor Tkachev,Christopher W. Peterson,Christopher W. Peterson,Alison Yu,Alison Yu,Hengqi Betty Zheng,Hengqi Betty Zheng,Hannah P. Gideon,Caylin G. Winchell,Philana Ling Lin,Philana Ling Lin,Colin D. Bingle,Scott B. Snapper,Scott B. Snapper,Jonathan A. Kropski,Jonathan A. Kropski,Fabian J. Theis,Herbert B. Schiller,Laure-Emmanuelle Zaragosi,Pascal Barbry,Alasdair Leslie,Alasdair Leslie,Hans-Peter Kiem,Hans-Peter Kiem,JoAnne L. Flynn,Sarah M. Fortune,Sarah M. Fortune,Sarah M. Fortune,Bonnie Berger,Robert W. Finberg,Leslie S. Kean,Leslie S. Kean,Manuel Garber,Aaron G. Schmidt,Aaron G. Schmidt,Daniel Lingwood,Alex K. Shalek,Jose Ordovas-Montanes,Nicholas E. Banovich,Alvis Brazma,Tushar J. Desai,Thu Elizabeth Duong,Oliver Eickelberg,Christine S. Falk,Michael Farzan,Ian A. Glass,Muzlifah Haniffa,Peter Horvath,Deborah T. Hung,Naftali Kaminski,Mark A. Krasnow,Malte Kühnemund,Robert Lafyatis,Haeock Lee,Sylvie Leroy,Sten Linnarson,Joakim Lundeberg,Kerstin B. Meyer,Alexander V. Misharin,Martijn C. Nawijn,Marko Nikolic,Dana Pe'er,Joseph E. Powell,Stephen R. Quake,Jay Rajagopal,Purushothama Rao Tata,Emma L. Rawlins,Aviv Regev,Paul A. Reyfman,Mauricio Rojas,Orit Rosen,Kourosh Saeb-Parsy,Christos Samakovlis,Herbert B. Schiller,Joachim L. Schultze,Max A. Seibold,Douglas P. Shepherd,Jason R. Spence,Avrum Spira,Xin Sun,Sarah A. Teichmann,Fabian J. Theis,Alexander M. Tsankov,Maarten van den Berge,Michael von Papen,Jeffrey A. Whitsett,Ramnik J. Xavier,Yan Xu,Kun Zhang +135 more
TL;DR: The data suggest that SARS-CoV-2 could exploit species-specific interferon-driven upregulation of ACE2, a tissue-protective mediator during lung injury, to enhance infection.
Journal ArticleDOI
Current best practices in single-cell RNA-seq analysis: a tutorial.
Malte D Luecken,Fabian J. Theis +1 more
TL;DR: The steps of a typical single‐cell RNA‐seq analysis, including pre‐processing (quality control, normalization, data correction, feature selection, and dimensionality reduction) and cell‐ and gene‐level downstream analysis, are detailed.
Journal ArticleDOI
RNA sequencing: the teenage years
TL;DR: Advances in RNA-sequencing technologies and methods over the past decade are discussed and adaptations that are enabling a fuller understanding of RNA biology are outlined, from when and where an RNA is expressed to the structures it adopts.
Journal ArticleDOI
COVID-19 severity correlates with airway epithelium-immune cell interactions identified by single-cell analysis.
Robert Lorenz Chua,Soeren Lukassen,Saskia Trump,Bianca P Hennig,Daniel Wendisch,Fabian Pott,Olivia Debnath,Loreen Thürmann,Florian Kurth,Florian Kurth,Maria Theresa Völker,Julia Kazmierski,Bernd Timmermann,Sven Twardziok,Stefan Schneider,Felix Machleidt,Holger Müller-Redetzky,Melanie Maier,Alexander Krannich,Sein Schmidt,Felix Balzer,Johannes Liebig,Jennifer Loske,Norbert Suttorp,Jürgen Eils,Naveed Ishaque,Uwe G. Liebert,Christof von Kalle,Andreas C. Hocke,Martin Witzenrath,Christine Goffinet,Christian Drosten,Sven Laudi,Irina Lehmann,Christian Conrad,Leif E. Sander,Roland Eils,Roland Eils +37 more
TL;DR: The data suggest that pharmacologic inhibition of the CCR1 and/or CCR5 pathways might suppress immune hyperactivation in critical COVID-19, which likely contribute to clinical observations of heightened inflammatory tissue damage, lung injury and respiratory failure.
Journal ArticleDOI
Single-Cell Transcriptomic Analysis of Human Lung Provides Insights into the Pathobiology of Pulmonary Fibrosis.
Paul A. Reyfman,James M. Walter,Nikita Joshi,Kishore R. Anekalla,Alexandra C. McQuattie-Pimentel,Stephen Chiu,Ramiro Fernandez,Mahzad Akbarpour,Ching I. Chen,Ziyou Ren,Rohan Verma,Hiam Abdala-Valencia,Kiwon Nam,Monica Chi,SeungHye Han,Francisco J. Gonzalez-Gonzalez,Saul Soberanes,Satoshi Watanabe,Kinola J.N. Williams,Annette S. Flozak,Trevor T. Nicholson,Vince K. Morgan,Deborah R. Winter,Monique Hinchcliff,Cara L. Hrusch,Robert D. Guzy,Catherine A. Bonham,Anne I. Sperling,Remzi Bag,Robert B. Hamanaka,Gökhan M. Mutlu,Anjana Yeldandi,Stacy A. Marshall,Ali Shilatifard,Luís A. Nunes Amaral,Harris Perlman,Jacob I. Sznajder,A. Christine Argento,Colin T. Gillespie,Jane Dematte,Manu Jain,Benjamin D. Singer,Karen M. Ridge,Anna P. Lam,Ankit Bharat,Sangeeta Bhorade,Cara J. Gottardi,G. R. Scott Budinger,Alexander V. Misharin +48 more
TL;DR: The results support the feasibility of discovery-based approaches using next-generation sequencing technologies to identify signaling pathways for targeting in the development of personalized therapies for patients with pulmonary fibrosis.
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