Comparison of the Transcriptomic Signatures of Skin and Lung Fibroblasts from Patients with Systemic Sclerosis

Abstract

Systemic Sclerosis (SSc) is a chronic autoimmune disease characterized by fibrosis in connective tissues. Fibroblasts are the effector cells of fibrosis since they contribute to the production of collagen and other extracellular matrix components. The goal of this study is to compare the transcriptomic profiles of primary human SSc skin and SSc lung fibroblasts. First, we conducted a meta-analysis of differentially expressed (DE) genes from two previously published differential analyses (SSc vs. normal) using skin and lung fibroblasts, observing 8.7% overlap in DE genes and 30% overlap in impacted pathways. Next, we characterized the signature of several genes of interest from the pro- and anti-fibrotic programs within the unique and overlap groups and explored overlapping drugs that are predicted to revert DE genes to “normal expression”. Finally, we identified 3760 DE genes between SSc lung and SSc skin fibroblasts, highlighting that fibroblasts in the disease state carry a tissue-specific signature that should be taken into consideration for therapeutic development. We also identified core genes that can serve as common targets for both skin and lung in SSc. To our knowledge, this is the first study to describe overlapping genes and pathways in primary human skin and lung fibroblasts from SSc patients.

Keywords

Systemic sclerosis / Scleroderma / Fibroblasts / Skin / Lung / RNA sequencing / Meta-analysis / Transcriptome

Supplementary Materials

The following supporting information can be found at: www.sciepublish.com/xxx/s1, Table S1: Genes of interest; Table S2: Meta-analysis DE genes; Table S3: Meta-analysis pathways; Table S4: DE genes in SSc lung vs. SSc skin fibroblasts; Table S5: Pathways in SSc lung vs. SSc skin fibroblasts.

Statement of the Use of Generative AI and AI-Assisted Technologies in the Writing Process

During the preparation of this manuscript, the authors used Copilot in order to summarize pathways and Gene Ontology terms from the lists generated by iPathwayGuide and to generate human body outline for the graphical abstract. After using this tool/service, the authors reviewed and edited the content as needed and take full responsibility for the content of the published article.

Acknowledgments

We thank the patients who graciously agreed to donate skin and lung tissues for this research.

Author Contributions

Conceptualization, C.A.F.-B. and L.R.; Validation, S.E.K. and L.R.; Formal Analysis, S.E.K. and L.R.; Investigation, S.E.K. and L.R.; Resources, C.A.F.-B. and L.R.; Data Curation, S.E.K. and L.R.; Writing—Original Draft Preparation, S.E.K. and L.R.; Writing—Review & Editing, C.A.F.-B., S.E.K. and L.R.; Visualization, S.E.K. and L.R.; Supervision, C.A.F.-B. and L.R.; Project Administration C.A.F.-B. and L.R.; Funding Acquisition, C.A.F.-B. and L.R.

Ethics Statement

The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Review Board of the University of Pittsburgh under IRB# 970946 (for lung tissues, renewed annually since 1997) and IRB# 0403072 (for skin tissues, renewed annually since 2004).

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study.

Data Availability Statement

Data is available from the corresponding authors upon reasonable request. The RNAseq data used in this study have been deposited in the NCBI Gene Expression Omnibus (GEO) under accession numbers GSE215841 and GSE153880.

Funding

This research was funded by the National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), grants number K01AR083019 and K24AR060297. The authors also would like to acknowledge the SmartState Center for Inflammation and Fibrosis Research and the Kitty Trask Holt Endowment at the Medical University of South Carolina (MUSC) for financial support.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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