CCR10+ epithelial cells from idiopathic pulmonary fibrosis lungs drive remodeling

Habiel, David M.; Espíndola, Milena S.; Jones, Isabelle; Coelho, Ana Lúcia; Stripp, Barry R.; Hogaboam, Cory M.

doi:10.1172/jci.insight.122211

Cited by 33 publications

(24 citation statements)

References 63 publications

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“…The scRNA-seq data for lung airway epithelial cells (LAECs) was downloaded from the GEO database using accession number GSE115982. The original data was generated in the study of [32] for CCR10 − and CCR10 + LAECs. We used the data generated from the CCR10 − cells with the sample identifier GSM3204305.…”

Section: Non-lcl Scrna-seq Data Setsmentioning

confidence: 99%

“…This data has been deposited in the NCBI Gene Expression Omnibus (GEO) database (accession number GSE126321). For the other two cell types, LAEC and DF, we obtained the scRNA-seq data for 3863 and 2553 cells from the studies of [32] and [33], respectively. In addition, we also processed two more samples for fibroblasts and one for iPSC cells (see Section 2.7. for data availability) to cross-validate our findings.…”

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confidence: 99%

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Single-Cell Expression Variability Implies Cell Function

Osorio

Zhong

et al. 2019

Cells

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As single-cell RNA sequencing (scRNA-seq) data becomes widely available, cell-to-cell variability in gene expression, or single-cell expression variability (scEV), has been increasingly appreciated. However, it remains unclear whether this variability is functionally important and, if so, what are its implications for multi-cellular organisms. Here, we analyzed multiple scRNA-seq data sets from lymphoblastoid cell lines (LCLs), lung airway epithelial cells (LAECs), and dermal fibroblasts (DFs) and, for each cell type, selected a group of homogenous cells with highly similar expression profiles. We estimated the scEV levels for genes after correcting the mean-variance dependency in that data and identified 465, 466, and 364 highly variable genes (HVGs) in LCLs, LAECs, and DFs, respectively. Functions of these HVGs were found to be enriched with those biological processes precisely relevant to the corresponding cell type’s function, from which the scRNA-seq data used to identify HVGs were generated—e.g., cytokine signaling pathways were enriched in HVGs identified in LCLs, collagen formation in LAECs, and keratinization in DFs. We repeated the same analysis with scRNA-seq data from induced pluripotent stem cells (iPSCs) and identified only 79 HVGs with no statistically significant enriched functions; the overall scEV in iPSCs was of negligible magnitude. Our results support the “variation is function” hypothesis, arguing that scEV is required for cell type-specific, higher-level system function. Thus, quantifying and characterizing scEV are of importance for our understating of normal and pathological cellular processes.

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Section: Non-lcl Scrna-seq Data Setsmentioning

confidence: 99%

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confidence: 99%

Single-Cell Expression Variability Implies Cell Function

Osorio

Zhong

et al. 2019

Cells

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“…First, EPHA3 is expressed predominantly in lymphocytes and encodes a receptor tyrosine kinase implicated in regulating cell adhesion and cellular motility [48]. A recent study demonstrated that a novel epithelial cell population derived from IPF lungs co-expressed EPHA3 and CC chemokine receptor (CCR)-10 and facilitated the development of lung remodeling [49]. CCL28, a chemokine ligand for CCR10, was upregulated in BALF in accordance with increased p38 activity ( Supplementary Table S1) [50].…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic Evaluation of Pulmonary Fibrosis-Related Genes: Utilization of Transgenic Mice with Modifying p38 Signal in the Lungs

Matsuda

Kim

Sugiyama

et al. 2020

IJMS

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Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing lung disease that is caused by the dysregulation of alveolar epithelial type II cells (AEC II). The mechanisms involved in the progression of IPF remain incompletely understood, although the immune response accompanied by p38 mitogen-activated protein kinase (MAPK) activation may contribute to some of them. This study aimed to examine the association of p38 activity in the lungs with bleomycin (BLM)-induced pulmonary fibrosis and its transcriptomic profiling. Accordingly, we evaluated BLM-induced pulmonary fibrosis during an active fibrosis phase in three genotypes of mice carrying stepwise variations in intrinsic p38 activity in the AEC II and performed RNA sequencing of their lungs. Stepwise elevation of p38 signaling in the lungs of the three genotypes was correlated with increased severity of BLM-induced pulmonary fibrosis exhibiting reduced static compliance and higher collagen content. Transcriptome analysis of these lung samples also showed that the enhanced p38 signaling in the lungs was associated with increased transcription of the genes driving the p38 MAPK pathway and differentially expressed genes elicited by BLM, including those related to fibrosis as well as the immune system. Our findings underscore the significance of p38 MAPK in the progression of pulmonary fibrosis.

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“…This data has been deposited in the NCBI GEO database (Accession number GSE126321, Data Availability). For the other two cell types, LAEC and DF, we obtained the scRNA-seq data for 3,863 and 2,553 cells from the studies of (Habiel et al 2018) and (Hagai et al 2018), respectively (Materials and Methods). All scRNA-seq data sets of the three cell types were produced using 10X Genomics droplet-based solution and made use of unique molecular identifiers (UMIs) (Kivioja et al 2011).…”

Section: Single-cell Rna Sequencing and Selection Of Highly Homogenoumentioning

confidence: 99%

“…The scRNA-seq data for lung airway epithelial cells (LAECs) was downloaded from the GEO database using accession number GSE115982. The original data was generated in the study of (Habiel et al 2018) for CCR10 -and CCR10 + LAECs. We used the data generated from the CCR10 -cells with the sample identifier GSM3204305.…”

Section: Non-lcl Scrna-seq Data Setsmentioning

confidence: 99%

Extent, heritability, and functional relevance of single cell expression variability in highly homogeneous populations of human cells

Osorio

Zhong

et al. 2019

Preprint

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Because of recent technological developments, single-cell assays such as single-cell RNA sequencing (scRNA-seq) have become much more widely available and have achieved unprecedented resolution in revealing cell heterogeneity. The extent of intrinsic cell-to-cell variability in gene expression, or single cell expression variability (scEV), has thus been increasingly appreciated. However, it remains unclear whether this variability is functionally important and, if so, what its implications are for multi-cellular organisms. We therefore analyzed multiple scRNA-seq data sets from lymphoblastoid cell lines (LCLs), lung airway epithelial cells (LAECs), and dermal fibroblasts (DFs). For each of the three cell types, we estimated scEV in homogeneous populations of cells; we identified 465, 466, and 291 highly variable genes (HVGs), respectively. These HVGs were enriched with specific functions precisely relevant to the cell types, from which the scRNA-seq data used to identify HVGs were generated-e.g., HVGs identified in lymphoblastoid cells were enriched in cytokine signaling pathways, LAECs collagen formation, and DFs keratinization. HVGs were deeply embedded in gene regulatory networks specific to corresponding cell types. We also found that scEV is a heritable trait, partially determined by cell donors' genetic makeups. Furthermore, across genes, especially immune genes, levels of scEV and between-individual variability in gene expression were positively correlated, suggesting a potential link between the two variabilities measured at different organizational levels. Taken together, our results support the "variation is function" hypothesis, which postulates that scEV is required for higher-level system function. Thus, we argue that quantifying and characterizing scEV in relevant cell types may deepen our understating of normal as well as pathological cellular processes.

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CCR10+ epithelial cells from idiopathic pulmonary fibrosis lungs drive remodeling

Cited by 33 publications

References 63 publications

Single-Cell Expression Variability Implies Cell Function

Single-Cell Expression Variability Implies Cell Function

Transcriptomic Evaluation of Pulmonary Fibrosis-Related Genes: Utilization of Transgenic Mice with Modifying p38 Signal in the Lungs

Extent, heritability, and functional relevance of single cell expression variability in highly homogeneous populations of human cells

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