Prognostic Model of Fibroblasts in Idiopathic Pulmonary Fibrosis by Combined Bulk and Single-cell RNA-sequencing

Overview

Journal Heliyon

Specialty Social Sciences

Date 2024 Aug 8

PMID 39113997

Authors

Jiarui Zhao

Chuanqing Jing

Rui Fan

Wei Zhang

Affiliations

Soon will be listed here.

Abstract

Background: Fibroblasts play an important role in the development of idiopathic pulmonary fibrosis (IPF).

Methods: We employed single-cell RNA-sequencing data obtained from the Gene Expression Omnibus database to perform cell clustering and annotation analyses. We then performed secondary clustering of fibroblasts and conducted functional enrichment and cell trajectory analyses of the two newly defined fibroblast subtypes. Bulk RNA-sequencing data were used to perform consensus clustering and weighted gene co-expression network analysis. We constructed a fibroblast-related prognostic model using least absolute shrinkage, selection operator regression, and Cox regression analysis. The prognostic model was validated using a validation dataset. Immune infiltration and functional enrichment analyses were conducted for patients in the high- and low-risk IPF groups.

Results: We characterized two fibroblast subtypes that are active in IPF (F3+ and ROBO2+). Using fibroblast-related genes, we identified five genes (, , , , and ) for the prognostic model. The area under the curve values of our prognostic model were 0.852, 0.859, and 0.844 at one, two, and three years in the training set, and 0.837, 0.758, and 0.821 at one, two, and three years in the validation set, respectively.

Conclusion: This study annotates and characterizes different subtypes of fibroblasts in IPF.

References

Kirillov V, Siler J, Ramadass M, Ge L, Davis J, Grant G . Sustained activation of toll-like receptor 9 induces an invasive phenotype in lung fibroblasts: possible implications in idiopathic pulmonary fibrosis. Am J Pathol. 2015; 185(4):943-57. DOI: 10.1016/j.ajpath.2014.12.011. View

Kim J, Kim J, Lee S, Kepreotis S, Yoo J, Chun J . Cytokine-Like 1 Regulates Cardiac Fibrosis via Modulation of TGF-β Signaling. PLoS One. 2016; 11(11):e0166480. PMC: 5105950. DOI: 10.1371/journal.pone.0166480. View

Wu T, Hu E, Xu S, Chen M, Guo P, Dai Z . clusterProfiler 4.0: A universal enrichment tool for interpreting omics data. Innovation (Camb). 2021; 2(3):100141. PMC: 8454663. DOI: 10.1016/j.xinn.2021.100141. View

Song J, Hong S, Lim C, Koh Y, Kim D . Acute exacerbation of idiopathic pulmonary fibrosis: incidence, risk factors and outcome. Eur Respir J. 2010; 37(2):356-63. DOI: 10.1183/09031936.00159709. View

Epstein Shochet G, Brook E, Israeli-Shani L, Edelstein E, Shitrit D . Fibroblast paracrine TNF-α signaling elevates integrin A5 expression in idiopathic pulmonary fibrosis (IPF). Respir Res. 2017; 18(1):122. PMC: 5477311. DOI: 10.1186/s12931-017-0606-x. View

Heinzelmann K, Lehmann M, Gerckens M, Noskovicova N, Frankenberger M, Lindner M . Cell-surface phenotyping identifies CD36 and CD97 as novel markers of fibroblast quiescence in lung fibrosis. Am J Physiol Lung Cell Mol Physiol. 2018; 315(5):L682-L696. DOI: 10.1152/ajplung.00439.2017. View

Rodriguez L, Emblom-Callahan M, Chhina M, Bui S, Aljeburry B, Tran L . Global Gene Expression Analysis in an in vitro Fibroblast Model of Idiopathic Pulmonary Fibrosis Reveals Potential Role for CXCL14/CXCR4. Sci Rep. 2018; 8(1):3983. PMC: 5838110. DOI: 10.1038/s41598-018-21889-7. View

Rosas I, Richards T, Konishi K, Zhang Y, Gibson K, Lokshin A . MMP1 and MMP7 as potential peripheral blood biomarkers in idiopathic pulmonary fibrosis. PLoS Med. 2008; 5(4):e93. PMC: 2346504. DOI: 10.1371/journal.pmed.0050093. View

Patel H, Shah J, Patel D, Avanthika C, Jhaveri S, Gor K . Idiopathic pulmonary fibrosis: Diagnosis, biomarkers and newer treatment protocols. Dis Mon. 2022; 69(7):101484. DOI: 10.1016/j.disamonth.2022.101484. View

10.

Wei K, Nguyen H, Brenner M . Fibroblast pathology in inflammatory diseases. J Clin Invest. 2021; 131(20). PMC: 8516469. DOI: 10.1172/JCI149538. View

11.

Jia G, Chandriani S, Abbas A, DePianto D, NDiaye E, Yaylaoglu M . CXCL14 is a candidate biomarker for Hedgehog signalling in idiopathic pulmonary fibrosis. Thorax. 2017; 72(9):780-787. DOI: 10.1136/thoraxjnl-2015-207682. View

12.

Galli J, Pandya A, Vega-Olivo M, Dass C, Zhao H, Criner G . Pirfenidone and nintedanib for pulmonary fibrosis in clinical practice: Tolerability and adverse drug reactions. Respirology. 2017; 22(6):1171-1178. DOI: 10.1111/resp.13024. View

13.

Xu M, Sun J, Yu Y, Pang Q, Lin X, Barakat M . TM4SF1 involves in miR-1-3p/miR-214-5p-mediated inhibition of the migration and proliferation in keloid by regulating AKT/ERK signaling. Life Sci. 2020; 254:117746. DOI: 10.1016/j.lfs.2020.117746. View

14.

Zhang H, Meltzer P, Davis S . RCircos: an R package for Circos 2D track plots. BMC Bioinformatics. 2013; 14:244. PMC: 3765848. DOI: 10.1186/1471-2105-14-244. View

15.

Kropski J, Blackwell T, Loyd J . The genetic basis of idiopathic pulmonary fibrosis. Eur Respir J. 2015; 45(6):1717-27. PMC: 4849867. DOI: 10.1183/09031936.00163814. View

16.

Wilkerson M, Hayes D . ConsensusClusterPlus: a class discovery tool with confidence assessments and item tracking. Bioinformatics. 2010; 26(12):1572-3. PMC: 2881355. DOI: 10.1093/bioinformatics/btq170. View

17.

Kirk T, Ahmed A, Rognoni E . Fibroblast Memory in Development, Homeostasis and Disease. Cells. 2021; 10(11). PMC: 8616330. DOI: 10.3390/cells10112840. View

18.

Newman A, Liu C, Green M, Gentles A, Feng W, Xu Y . Robust enumeration of cell subsets from tissue expression profiles. Nat Methods. 2015; 12(5):453-7. PMC: 4739640. DOI: 10.1038/nmeth.3337. View

19.

McAnulty R . Fibroblasts and myofibroblasts: their source, function and role in disease. Int J Biochem Cell Biol. 2007; 39(4):666-71. DOI: 10.1016/j.biocel.2006.11.005. View

20.

Qiu X, Mao Q, Tang Y, Wang L, Chawla R, Pliner H . Reversed graph embedding resolves complex single-cell trajectories. Nat Methods. 2017; 14(10):979-982. PMC: 5764547. DOI: 10.1038/nmeth.4402. View