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Integrating bulk and single-cell sequencing reveals the phenotype-associated cell subpopulations in sepsis-induced acute lung injury.

ABSTRACT: The dysfunctional immune response and multiple organ injury in sepsis is a recurrent theme impacting prognosis and mortality, while the lung is the first organ invaded by sepsis. To systematically elucidate the transcriptomic changes in the main constituent cells of sepsis-injured lung tissue, we applied single-cell RNA sequencing to the lung tissue samples from septic and control mice and created a comprehensive cellular landscape with 25044 cells, including 11317 immune and 13727 non-immune cells. Sepsis alters the composition of all cellular compartments, particularly neutrophils, monocytes, T cells, endothelial, and fibroblasts populations. Our study firstly provides a single-cell view of cellular changes in septic lung injury. Furthermore, by integrating bulk sequencing data and single-cell data with the Scissors-method, we identified the cell subpopulations that are most associated with septic lung injury phenotype. The phenotypic-related cell subpopulations identified by Scissors-method were consistent with the cell subpopulations with significant composition changes. The function analysis of the differentially expressed genes (DEGs) and the cell-cell interaction analysis further reveal the important role of these phenotype-related subpopulations in septic lung injury. Our research provides a rich resource for understanding cellular changes and provides insights into the contributions of specific cell types to the biological processes that take place during sepsis-induced lung injury.

SUBMITTER: Wang F

PROVIDER: S-EPMC9666384 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Integrating bulk and single-cell sequencing reveals the phenotype-associated cell subpopulations in sepsis-induced acute lung injury.

Wang Fuquan F Chen Ming M Ma Jiamin J Wang Chenchen C Wang Jingxu J Xia Haifa H Zhang Dingyu D Yao Shanglong S

Frontiers in immunology 20221102

The dysfunctional immune response and multiple organ injury in sepsis is a recurrent theme impacting prognosis and mortality, while the lung is the first organ invaded by sepsis. To systematically elucidate the transcriptomic changes in the main constituent cells of sepsis-injured lung tissue, we applied single-cell RNA sequencing to the lung tissue samples from septic and control mice and created a comprehensive cellular landscape with 25044 cells, including 11317 immune and 13727 non-immune ce ...[more]

PMID: 36405762

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Project description:BackgroundThe only therapeutic options that exist for squamous cell lung carcinoma (SCC) are standard radiation and cytotoxic chemotherapy. Cancer stem cells (CSCs) are hypothesized to account for therapeutic resistance, suggesting that CSCs must be specifically targeted. Here, we analyze the transcriptome of CSC and non-CSC subpopulations by RNA-seq to identify new potential therapeutic strategies for SCC.MethodsWe sorted a SCC into CD133- and CD133+ subpopulations and then examined both by copy number analysis (CNA) and whole genome and transcriptome sequencing. We analyzed The Cancer Genome Atlas (TCGA) transcriptome data of 221 SCCs to determine the generality of our observations.ResultsBoth subpopulations highly expressed numerous mRNA isoforms whose protein products are active drug targets for other cancers; 31 (25%) correspond to 18 genes under active investigation as mAb targets and an additional 4 (3%) are of therapeutic interest. Moreover, we found evidence that both subpopulations were proliferatively driven by very high levels of c-Myc and the TRAIL long isoform (TRAILL) and that normal apoptotic responses to high expression of these genes was prevented through high levels of Mcl-1L and Bcl-xL and c-FlipL-isoforms for which drugs are now in clinical development. SCC RNA-seq data (n?=?221) from TCGA supported our findings. Our analysis is inconsistent with the CSC concept that most cells in a cancer have lost their proliferative potential. Furthermore, our study suggests how to target both the CSC and non-CSC subpopulations with one treatment strategy.ConclusionsOur study is relevant to SCC in particular for it presents numerous potential options to standard therapy that target the entire tumor. In so doing, it demonstrates how transcriptome sequencing provides insights into the molecular underpinnings of cancer propagating cells that, importantly, can be leveraged to identify new potential therapeutic options for cancers beyond what is possible with DNA sequencing.

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Integrating bulk and single-cell sequencing reveals the phenotype-associated cell subpopulations in sepsis-induced acute lung injury.

Publications

Integrating bulk and single-cell sequencing reveals the phenotype-associated cell subpopulations in sepsis-induced acute lung injury.

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