Single-Cell Transcriptomic Analysis of Human Lung Provides Insights into the Pathobiology of Pulmonary Fibrosis

Reyfman, Paul A.; Walter, James M.; Joshi, Nikita; Anekalla, Kishore R.; McQuattie‐Pimentel, Alexandra C.; Chiu, Stephen; Fernández, Ramiro; Akbarpour, Mahzad; Chen, Ching-I; Ren, Ziyou; Verma, Rohan; Abdala‐Valencia, Hiam; Nam, Ki-Won; Chi, Monica; Han, Sae Hwang; González-González, Francisco J.; Soberanes, Saul; Watanabe, Satoshi; Williams, Kibileri; Flozak, Annette S.; Nicholson, Trevor T.; Morgan, Vince K.; Winter, Deborah R.; Hinchcliff, Monique; Hrusch, Cara L.; Guzy, Robert D.; Bonham, Catherine A.; Sperling, Anne I.; Bag, Remzi; Hamanaka, Robert B.; Mutlu, Gökhan M.; Yeldandi, Anjana V.; Marshall, Stacy A.; Shilatifard, Ali; Amaral, Luı́s A. Nunes; Perlman, Harris; Sznajder, Jacob I.; Argento, A. Christine; Gillespie, Colin T.; Dematte, Jane; Jain, Manu; Singer, Benjamin D.; Ridge, Karen M.; Lam, Anna; Bharat, Ankit; Bhorade, Sangeeta; Gottardi, Cara J.; Budinger, G.S.; Misharin, Alexander V.

doi:10.1164/rccm.201712-2410oc

Cited by 1,038 publications

(1,216 citation statements)

References 57 publications

(71 reference statements)

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“…Expansion of alveolar macrophages has also been observed in human lung tissue from patients with pulmonary fibrosis compared to healthy controls . Similar to findings in mice, single‐cell RNA sequencing revealed multiple distinct macrophage populations in lungs of patients with fibrosis …”

Section: Innate Immune Cells and The Pathogenesis Of Lung Fibrosissupporting

confidence: 65%

“…Of note are recent findings identifying direct interactions between macrophages and myofibroblasts via cadherin‐11, which possibly mediate the Mo‐AM localisation to the profibrotic niche, and importantly, specific deletion of Mo‐AMs was found to ameliorate fibrosis . These findings are further supported in human studies, wherein macrophages isolated from the lungs of IPF patients expressed similar profibrotic genes as their murine Mo‐AM homologs …”

Section: Innate Immune Cells and The Pathogenesis Of Lung Fibrosismentioning

confidence: 60%

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A pathologic two‐way street: how innate immunity impacts lung fibrosis and fibrosis impacts lung immunity

2019

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Lung fibrosis is characterised by the accumulation of extracellular matrix within the lung and is secondary to both known and unknown aetiologies. This accumulation of scar tissue limits gas exchange causing respiratory insufficiency. The pathogenesis of lung fibrosis is poorly understood, but immunologic‐based treatments have been largely ineffective. Despite this, accumulating evidence suggests that innate immune cells and receptors play important modulatory roles in the initiation and propagation of the disease. Paradoxically, while innate immune signalling may be important for the pathogenesis of fibrosis, there is also evidence to suggest that innate immune function against pathogens may be impaired, leading to dysregulated and/or impaired host defence. This review summarises the evidence for this pathologic two‐way street, highlights new concepts of pathogenesis and recommends future directions for research emphasis.

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Section: Innate Immune Cells and The Pathogenesis Of Lung Fibrosissupporting

confidence: 65%

Section: Innate Immune Cells and The Pathogenesis Of Lung Fibrosismentioning

confidence: 60%

A pathologic two‐way street: how innate immunity impacts lung fibrosis and fibrosis impacts lung immunity

2019

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“…GEO (https://www.ncbi.nlm.nih.gov/geo/) or Human Cell Atlas (https://www.humancellatlas.org). Totally, we curated single cell gene expression matrices of 13 human tissues, including lung [8], liver [9], ileum [10], rectum [10], blood [11], bone marrow [12], skin [13], spleen [14], esophagus [14], colon [15], eye [16], stomach [17] and kidney [18] (Table S1). For each tissue, we performed cell clustering and dimension reduction on the scaled gene expression matrix using Seurat package [19].…”

Section: Cell Type Identification In 13 Human Tissuesmentioning

confidence: 99%

Single cell RNA sequencing of 13 human tissues identify cell types and receptors of human coronaviruses

Shen

Zhang

et al. 2020

Biochemical and Biophysical Research Communications

838

774

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a b s t r a c tThe new coronavirus (SARS-CoV-2) outbreak from December 2019 in Wuhan, Hubei, China, has been declared a global public health emergency. Angiotensin I converting enzyme 2 (ACE2), is the host receptor by SARS-CoV-2 to infect human cells. Although ACE2 is reported to be expressed in lung, liver, stomach, ileum, kidney and colon, its expressing levels are rather low, especially in the lung. SARS-CoV-2 may use co-receptors/auxiliary proteins as ACE2 partner to facilitate the virus entry. To identify the potential candidates, we explored the single cell gene expression atlas including 119 cell types of 13 human tissues and analyzed the single cell co-expression spectrum of 51 reported RNA virus receptors and 400 other membrane proteins. Consistent with other recent reports, we confirmed that ACE2 was mainly expressed in lung AT2, liver cholangiocyte, colon colonocytes, esophagus keratinocytes, ileum ECs, rectum ECs, stomach epithelial cells, and kidney proximal tubules. Intriguingly, we found that the candidate co-receptors, manifesting the most similar expression patterns with ACE2 across 13 human tissues, are all peptidases, including ANPEP, DPP4 and ENPEP. Among them, ANPEP and DPP4 are the known receptors for human CoVs, suggesting ENPEP as another potential receptor for human CoVs. We also conducted "CellPhoneDB" analysis to understand the cell crosstalk between CoV-targets and their surrounding cells across different tissues. We found that macrophages frequently communicate with the CoVs targets through chemokine and phagocytosis signaling, highlighting the importance of tissue macrophages in immune defense and immune pathogenesis.

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“…We analyzed the expression of TRIB3, HAPLN2, and ACE2, in different lung cell populations by using two previously published human single-cell RNA-seq data (Table S4) 19,20 . The first dataset 20 was explored in the UCSC Cell Browser (http://nupulmonary.org/resources/), aiming the identification of the cell populations expressing those genes. The samples with pulmonary fibrosis presented in this dataset were omitted from our analysis, and only non-diseased lung samples were included (n=8).…”

Section: Single-cell Analysis Of Human Lung Datasetsmentioning

confidence: 99%

“…The reanalysis of lung single-cell RNA sequencing data 19,20 demonstrated TRIB3 expressed mainly in alveolar type I (AT1) and type II (AT2) cells and in ciliated cells ( Figure 1d-f, Figure S3), which also express SARS-CoV-2 receptor ACE2 7,8,21 . The involvement of TRIB3 in viral infection is poorly understood; however, its inhibition was associated with an increase of hepatitis C virus (HCV) replication 22 .…”

Section: Introductionmentioning

confidence: 99%

Prediction of SARS-CoV interaction with host proteins during lung aging reveals a potential role for TRIB3 in COVID-19

Moraes

Paiva

Cury

et al. 2020

Preprint

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COVID-19 is prevalent in the elderly. Old individuals are more likely to develop pneumonia and respiratory failure due to alveolar damage, suggesting that lung senescence may increase the susceptibility to SARS-CoV-2 infection and replication. Considering that human coronavirus (HCoVs; SARS-CoV-2 and SARS-CoV) require host cellular factors for infection and replication, we analyzed Genotype-Tissue Expression (GTEx) data to test whether lung aging is associated with transcriptional changes in human protein-coding genes that potentially interact with these viruses.We found decreased expression of the gene tribbles homolog 3 (TRIB3) during aging in male individuals, and its protein was predicted to interact with HCoVs nucleocapsid protein and RNAdependent RNA polymerase. Using publicly available lung single-cell data, we found TRIB3 expressed mainly in alveolar epithelial cells that express SARS-CoV-2 receptor ACE2. Functional enrichment analysis of age-related genes, in common with SARS-CoV-induced perturbations, revealed genes associated with the mitotic cell cycle and surfactant metabolism. Given that TRIB3 was previously reported to decrease virus infection and replication, the decreased expression of TRIB3 in aged lungs may help explain why older male patients are related to more severe cases of the COVID-19. Thus, drugs that stimulate TRIB3 expression should be evaluated as a potential therapy for the disease.

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Single-Cell Transcriptomic Analysis of Human Lung Provides Insights into the Pathobiology of Pulmonary Fibrosis

Cited by 1,038 publications

References 57 publications

A pathologic two‐way street: how innate immunity impacts lung fibrosis and fibrosis impacts lung immunity

A pathologic two‐way street: how innate immunity impacts lung fibrosis and fibrosis impacts lung immunity

Single cell RNA sequencing of 13 human tissues identify cell types and receptors of human coronaviruses

Prediction of SARS-CoV interaction with host proteins during lung aging reveals a potential role for TRIB3 in COVID-19

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