scholarly journals Single-cell analysis reveals fibroblast heterogeneity and myofibroblasts in systemic sclerosis-associated interstitial lung disease

2019 ◽  
Vol 78 (10) ◽  
pp. 1379-1387 ◽  
Author(s):  
Eleanor Valenzi ◽  
Melissa Bulik ◽  
Tracy Tabib ◽  
Christina Morse ◽  
John Sembrat ◽  
...  
Keyword(s):  
Gene Expression ◽  
Systemic Sclerosis ◽  
Interstitial Lung Disease ◽  
Lung Disease ◽  
Single Cell ◽  
Mesenchymal Cell ◽  
Mesenchymal Cells ◽  
Cell Populations ◽  
Healthy Control ◽  
Fibroblast Heterogeneity

ObjectivesMyofibroblasts are key effector cells in the extracellular matrix remodelling of systemic sclerosis-associated interstitial lung disease (SSc-ILD); however, the diversity of fibroblast populations present in the healthy and SSc-ILD lung is unknown and has prevented the specific study of the myofibroblast transcriptome. We sought to identify and define the transcriptomes of myofibroblasts and other mesenchymal cell populations in human healthy and SSc-ILD lungs to understand how alterations in fibroblast phenotypes lead to SSc-ILD fibrosis.MethodsWe performed droplet-based, single-cell RNA-sequencing with integrated canonical correlation analysis of 13 explanted lung tissue specimens (56 196 cells) from four healthy control and four patients with SSc-ILD, with findings confirmed by cellular indexing of transcriptomes and epitopes by sequencing in additional samples.ResultsExamination of gene expression in mesenchymal cells identified two major, SPINT2hi and MFAP5hi, and one minor, WIF1hi, fibroblast populations in the healthy control lung. Combined analysis of control and SSc-ILD mesenchymal cells identified SPINT2hi, MFAP5hi, few WIF1hi fibroblasts and a new large myofibroblast population with evidence of actively proliferating myofibroblasts. We compared differential gene expression between all SSc-ILD and control mesenchymal cell populations, as well as among the fibroblast subpopulations, showing that myofibroblasts undergo the greatest phenotypic changes in SSc-ILD and strongly upregulate expression of collagens and other profibrotic genes.ConclusionsOur results demonstrate previously unrecognised fibroblast heterogeneity in SSc-ILD and healthy lungs, and define multimodal transcriptome-phenotypes associated with these populations. Our data indicate that myofibroblast differentiation and proliferation are key pathological mechanisms driving fibrosis in SSc-ILD.

scholarly journals Patients with systemic sclerosis-associated pulmonary arterial hypertension express a genomic signature distinct from patients with interstitial lung disease

2018 ◽  
Vol 3 (3) ◽  
pp. 242-248 ◽  
Author(s):  
Matthew Moll ◽  
Romy B Christmann ◽  
Yuqing Zhang ◽  
Michael L Whitfield ◽  
Yu Mei Wang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Systemic Sclerosis ◽  
Pulmonary Arterial Hypertension ◽  
Interstitial Lung Disease ◽  
Arterial Hypertension ◽  
Lung Disease ◽  
Expression Profiles ◽  
Area Under The Curve ◽  
Gene Expression Profiles ◽  
Pulmonary Arterial

Objective: Pulmonary arterial hypertension and interstitial lung disease are major causes of mortality in systemic sclerosis. We used a previously identified microarray biomarker to determine whether systemic sclerosis-pulmonary arterial hypertension and systemic sclerosis-interstitial lung disease patients demonstrate distinct gene expression profiles. Methods: Peripheral blood mononuclear cells were collected from healthy controls ( n = 10), systemic sclerosis patients without pulmonary hypertension (systemic sclerosis-no pulmonary arterial hypertension, n = 39), and systemic sclerosis-pulmonary arterial hypertension patients ( n = 21; mean pulmonary arterial pressure ≥25, pulmonary capillary wedge pressure ≤15, and pulmonary vascular resistance ≥3 Wood units) diagnosed by right heart catheterization. Systemic sclerosis-interstitial lung disease patients were defined as those with evidence of fibrosis on chest computed tomography and significant restriction (forced vital capacity <70% predicted, n = 11). Systemic sclerosis-pulmonary arterial hypertension biomarker included 69 genes selected by unbiased statistical screening of three publicly available microarray studies. RNA levels were measured by NanoString Technologies. Gene expression levels that were significantly correlated with pulmonary arterial hypertension (multiple statistical measures) were chosen as inputs into a forward selection logistic regression model. Results: When interstitial lung disease patients were included ( n = 64), four genes (S100P, CD8B1, CCL2, and TIMP1) and male sex predicted pulmonary arterial hypertension with a high level of accuracy (area under the curve = 0.83). Without interstitial lung disease patients ( n = 53), two genes (THBS1 and CD8B1) and male sex predicted pulmonary arterial hypertension with a high level of accuracy (area under the curve = 0.80). When examining systemic sclerosis patients with borderline elevated pulmonary pressures (mean pulmonary arterial pressure = 21–24 mmHg), gene expression changes closely resembled the systemic sclerosis-pulmonary arterial hypertension group, except for THBS1. Conclusion: Systemic sclerosis-pulmonary arterial hypertension and systemic sclerosis-interstitial lung disease have similar but distinct gene expression profiles. Many gene expression changes occur early in the disease course, potentially allowing early detection. THBS1 appears to be an important mediator in the development of pulmonary arterial hypertension-predominant phenotype. Further prospective investigation is warranted.

scholarly journals Endothelial Cells Expressing Endothelial and Mesenchymal Cell Gene Products in Lung Tissue From Patients With Systemic Sclerosis-Associated Interstitial Lung Disease

2015 ◽  
Vol 68 (1) ◽  
pp. 210-217 ◽  
Author(s):  
Fabian A. Mendoza ◽  
Sonsoles Piera-Velazquez ◽  
John L. Farber ◽  
Carol Feghali-Bostwick ◽  
Sergio A. Jiménez
Keyword(s):  
Endothelial Cells ◽  
Systemic Sclerosis ◽  
Interstitial Lung Disease ◽  
Lung Disease ◽  
Lung Tissue ◽  
Mesenchymal Cell ◽  
Gene Products ◽  
Cell Gene

scholarly journals Novel lung imaging biomarkers and skin gene expression subsetting in dasatinib treatment of systemic sclerosis-associated interstitial lung disease

PLoS ONE ◽  
2017 ◽  
Vol 12 (11) ◽  
pp. e0187580 ◽  
Author(s):  
Viktor Martyanov ◽  
Grace-Hyun J. Kim ◽  
Wendy Hayes ◽  
Shuyan Du ◽  
Bishu J. Ganguly ◽  
...  
Keyword(s):  
Gene Expression ◽  
Systemic Sclerosis ◽  
Interstitial Lung Disease ◽  
Lung Disease ◽  
Lung Imaging ◽  
Imaging Biomarkers ◽  
Dasatinib Treatment

scholarly journals Disparate Interferon Signaling and Shared Aberrant Basaloid Cells in Single-Cell Profiling of Idiopathic Pulmonary Fibrosis and Systemic Sclerosis-Associated Interstitial Lung Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Eleanor Valenzi ◽  
Tracy Tabib ◽  
Anna Papazoglou ◽  
John Sembrat ◽  
Humberto E. Trejo Bittar ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Interstitial Lung Disease ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Lung Disease ◽  
Single Cell ◽  
Alveolar Type ◽  
Type I ◽  
Interferon Signaling ◽  
Mesenchymal Transition

Idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-associated interstitial lung disease (SSc-ILD) differ in the predominant demographics and identified genetic risk alleles of effected patients, however both diseases frequently progress to respiratory failure and death. Contrasting advanced SSc-ILD to IPF provides insight to the role dysregulated immunity may play in pulmonary fibrosis. To analyze cell-type specific transcriptome commonalities and differences between IPF and SSc-ILD, we compared single-cell RNA-sequencing (scRNA-seq) of 21 explanted lung tissue specimens from patients with advanced IPF, SSc-ILD, and organ donor controls. Comparison of IPF and SSc-ILD tissue identified divergent patterns of interferon signaling, with interferon-gamma signaling upregulated in the SPP1hi and FABP4hi macrophages, cytotoxic T cells, and natural kill cells of IPF, while type I interferon signaling and production was upregulated in the corresponding SSc-ILD populations. Plasmacytoid dendritic cells were found in diseased lungs only, and exhibited upregulated cellular stress pathways in SSc-ILD compared to IPF. Alveolar type I cells were dramatically decreased in both IPF and SSc-ILD, with a distinct transcriptome signature separating these cells by disease. KRT5-/KRT17+ aberrant basaloid cells exhibiting markers of cellular senescence and epithelial-mesenchymal transition were identified in SSc-ILD for the first time. In summary, our study utilizes the enriched capabilities of scRNA-seq to identify key divergent cell types and pathways between IPF and SSc-ILD, providing new insights into the shared and distinct mechanisms between idiopathic and autoimmune interstitial lung diseases.

scholarly journals Screening and identification of potential biomarkers and therapeutic targets for systemic sclerosis-associated interstitial lung disease

2021 ◽  
Author(s):  
Biqing Huang ◽  
Jing Li ◽  
Jiuliang Zhao
Keyword(s):  
Gene Expression ◽  
Systemic Sclerosis ◽  
Interstitial Lung Disease ◽  
Lung Disease ◽  
Matrix Protein ◽  
Differential Expression Analysis ◽  
Therapeutic Targets ◽  
Rank Aggregation ◽  
Lung Fibroblasts ◽  
Potential Biomarkers

Objectives: This study aims to analyze gene expression in lung tissue and lung fibroblasts of patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) to identify potential biomarkers and therapeutic targets and to examine its possible role in the pathogenesis of SSc-ILD. Patients and methods: We obtained datasets from Gene Expression Omnibus (GEO) database, and used Robust Rank Aggregation to calculate the co-expressed differentially-expressed-genes (DEGs) in three chips, then analyzed the function, signaling pathways and the protein-protein interaction network of the DEGs. Finally, we verified the DEGs related to SSc-ILD by three databases of Comparative Toxicogenomics Database (CTD), GENE, and DisGeNET, respectively. Results: There were 16 co-expressed DEGs related to SSc-ILD in three GEO series, of which six genes were upregulated, and 10 genes were downregulated. The CTD included 29,936 genes related to SSc, and the GENE and DisGeNET databases had 429 genes related to SSc. Conclusion: The results of gene differential expression analysis suggest that interleukin-6, chemokine ligand 2, intercellular adhesion molecule 1, tumor necrosis factor alpha-induced protein 3, pentraxin 3, and cartilage oligomeric matrix protein may be implicated in the pathogenesis of SSc-ILD and are expected to be potential biomarkers and therapeutic targets for SSc-ILD.

scholarly journals Skin Gene Expression Correlates of Severity of Interstitial Lung Disease in Systemic Sclerosis

2013 ◽  
Vol 65 (11) ◽  
pp. 2917-2927 ◽  
Author(s):  
Shervin Assassi ◽  
Minghua Wu ◽  
Filemon K. Tan ◽  
Jeffrey Chang ◽  
Tiffany A. Graham ◽  
...  
Keyword(s):  
Gene Expression ◽  
Systemic Sclerosis ◽  
Interstitial Lung Disease ◽  
Lung Disease
Sign in / Sign up

Export Citation Format

Share Document