A cellular census of human lungs identifies novel cell states in health and in asthma

Braga, Felipe A. Vieira; Kar, Gozde; Berg, Marijn; Carpaij, Orestes A; Polański, Krzysztof; Simon, Lukas M.; Brouwer, Sharon; Gomes, Tomás; Hesse, Laura; Jiang, Jian; Fasouli, Eirini S.; Efremova, Mirjana; Vento‐Tormo, Roser; Talavera-López, Carlos; Jonker, Marnix; Affleck, Karen; Palit, Subarna; Strzelecka, Paulina M.; Firth, Helen V.; Mahbubani, Krishnaa T.; Cvejic, Ana; Meyer, Kerstin B.; Saeb‐Parsy, Kourosh; Luinge, Marjan; Brandsma, Corry‐Anke; Timens, Wim; Angelidis, Ilias; Strunz, Maximilian; Koppelman, Gerard H.; Oosterhout, Antoon J. van; Schiller, Herbert B.; Theis, Fabian J.; Berge, Maarten van den; Nawijn, Martijn C.; Teichmann, Sarah A.

doi:10.1038/s41591-019-0468-5

Cited by 728 publications

(813 citation statements)

References 51 publications

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“…We identified 80 aberrant basaloid cells in this data and observed greater correlation between them from each dataset (Spearman's rho: 0.81), than with 90 epithelial cells within each dataset ( Figure 2E ). Re-analysis of a recently published scRNAseq dataset that contained normal airway and lung 6 parenchyma samples (23) confirmed that genes specific to the pVE were not observed in distal lung VE ( Fig. 3E).…”

Section: Resultssupporting

confidence: 60%

“…In IPF lungs, COL15A1+ CD31+ VE cells are observed in the distal lung, typically at the parenchymal edge of fibroblastic foci and in areas of bronchiolization ( Fig 3D). Re-analysis of a recently published scRNAseq dataset that contained normal airway and lung parenchyma samples 110 (23) confirmed that genes specific to the pVE were not observed in distal lung VE ( Fig. 3E).…”

mentioning

confidence: 53%

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Single Cell RNA-seq reveals ectopic and aberrant lung resident cell populations in Idiopathic Pulmonary Fibrosis

Adams

Schupp

Poli

et al. 2019

Preprint

247

499

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We provide a single cell atlas of Idiopathic Pulmonary Fibrosis (IPF), a fatal interstitial lung disease, focusing on resident lung cell populations. By profiling 312,928 cells from 32 IPF, 29 healthy control and 18 chronic obstructive pulmonary disease (COPD) lungs, we demonstrate that IPF is characterized by changes in discrete subpopulations of cells in the three major parenchymal compartments: the epithelium, endothelium and stroma. Among epithelial cells, we identify a novel population of IPF enriched aberrant basaloid cells that co-express basal epithelial markers, mesenchymal markers, senescence markers, developmental transcription factors and are located at the edge of myofibroblast foci in the IPF lung. Among vascular endothelial cells in the in IPF lung parenchyma we identify an expanded cell population transcriptomically identical to vascular endothelial cells normally restricted to the bronchial circulation. We confirm the presence of both populations by immunohistochemistry and independent datasets. Among stromal cells we identify fibroblasts and myofibroblasts in both control and IPF lungs and leverage manifold-based algorithms diffusion maps and diffusion pseudotime to infer the origins of the activated IPF myofibroblast. Our work provides a comprehensive catalogue of the aberrant cellular transcriptional programs in IPF, demonstrates a new framework for analyzing complex disease with scRNAseq, and provides the largest lung disease single-cell atlas to date.

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Section: Resultssupporting

confidence: 60%

mentioning

confidence: 53%

Single Cell RNA-seq reveals ectopic and aberrant lung resident cell populations in Idiopathic Pulmonary Fibrosis

Adams

Schupp

Poli

et al. 2019

Preprint

247

499

View full text Add to dashboard Cite

show abstract

“…4). Furthermore, by examining data from two single-cell RNA-seq studies [17,18], we only identified 2 out of 4599 and 13 out of 540 lung epithelial cells expressed a detectable level of ACE2 (www.ebi.ac.uk/gxa/sc). This confirms that the overall expression of ACE2 in the lung is low and may also suggest the presence of selected cells with upregulated ACE2 expression under certain conditions.…”

Section: Expression Of Ace2 In Human Tissues and Implications For Virmentioning

confidence: 99%

Structure analysis of the receptor binding of 2019-nCoV

Chen

Guo

Pan

et al. 2020

Biochemical and Biophysical Research Communications

736

705

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a b s t r a c t2019-nCoV is a newly identified coronavirus with high similarity to SARS-CoV. We performed a structural analysis of the receptor binding domain (RBD) of spike glycoprotein responsible for entry of coronaviruses into host cells. The RBDs from the two viruses share 72% identity in amino acid sequences, and molecular simulation reveals highly similar ternary structures. However, 2019-nCoV has a distinct loop with flexible glycyl residues replacing rigid prolyl residues in SARS-CoV. Molecular modeling revealed that 2019-nCoV RBD has a stronger interaction with angiotensin converting enzyme 2 (ACE2). A unique phenylalanine F486 in the flexible loop likely plays a major role because its penetration into a deep hydrophobic pocket in ACE2. ACE2 is widely expressed with conserved primary structures throughout the animal kingdom from fish, amphibians, reptiles, birds, to mammals. Structural analysis suggests that ACE2 from these animals can potentially bind RBD of 2019-nCoV, making them all possible natural hosts for the virus. 2019-nCoV is thought to be transmitted through respiratory droplets. However, since ACE2 is predominantly expressed in intestines, testis, and kidney, fecal-oral and other routes of transmission are also possible. Finally, antibodies and small molecular inhibitors that can block the interaction of ACE2 with RBD should be developed to combat the virus.

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“…It has recently been demonstrated through single cell sequencing analysis (scSeq) that cells from the human upper airway -including nasal RE goblet, basal and ciliated cells -express high levels of ACE2 and TMPRSS2, suggesting that these RE cell types may serve as a viral reservoir during CoV-2 infection 45 . However, the analyzed samples did not include any OSNs or sustentacular cells, suggesting that tissue sampling in these experiments was limited to the RE and did not access the OE 46,47 .…”

Section: Introductionmentioning

confidence: 99%

Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia

Brann

Tsukahara

Weinreb

et al. 2020

Preprint

294

346

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Recent reports suggest an association between COVID-19 and altered olfactory function. Here we analyze bulk and single cell RNA-Seq datasets to identify cell types in the olfactory epithelium that express molecules that mediate infection by SARS-CoV-2 (CoV-2), the causal agent in COVID-19. We find in both mouse and human datasets that olfactory sensory neurons do not express two key genes involved in CoV-2 entry, ACE2 and TMPRSS2. In contrast, olfactory epithelial support cells and stem cells express both of these genes, as do cells in the nasal respiratory epithelium. Taken together, these findings suggest possible mechanisms through which CoV-2 infection could lead to anosmia or other forms of olfactory dysfunction.

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A cellular census of human lungs identifies novel cell states in health and in asthma

Cited by 728 publications

References 51 publications

Single Cell RNA-seq reveals ectopic and aberrant lung resident cell populations in Idiopathic Pulmonary Fibrosis

Single Cell RNA-seq reveals ectopic and aberrant lung resident cell populations in Idiopathic Pulmonary Fibrosis

Structure analysis of the receptor binding of 2019-nCoV

Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia

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