Journal article
Cloning a profibrotic stem cell variant in idiopathic pulmonary fibrosis
Science translational medicine, Vol.15(693), eabp9528
04/26/2023
DOI: 10.1126/scitranslmed.abp9528
PMCID: PMC10794039
PMID: 37099633
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible, and rapidly fatal interstitial lung disease marked by the replacement of lung alveoli with dense fibrotic matrices. Although the mechanisms initiating IPF remain unclear, rare and common alleles of genes expressed in lung epithelia, combined with aging, contribute to the risk for this condition. Consistently, single-cell RNA sequencing (scRNA-seq) studies have identified lung basal cell heterogeneity in IPF that might be pathogenic. We used single-cell cloning technologies to generate "libraries" of basal stem cells from the distal lungs of 16 patients with IPF and 10 controls. We identified a major stem cell variant that was distinguished from normal stem cells by its ability to transform normal lung fibroblasts into pathogenic myofibroblasts in vitro and to activate and recruit myofibroblasts in clonal xenografts. This profibrotic stem cell variant, which was shown to preexist in low quantities in normal and even fetal lungs, expressed a broad network of genes implicated in organ fibrosis and showed overlap in gene expression with abnormal epithelial signatures identified in previously published scRNA-seq studies of IPF. Drug screens highlighted specific vulnerabilities of this profibrotic variant to inhibitors of epidermal growth factor and mammalian target of rapamycin signaling as prospective therapeutic targets. This profibrotic stem cell variant in IPF was distinct from recently identified profibrotic stem cell variants in chronic obstructive pulmonary disease and may extend the notion that inappropriate accrual of minor and preexisting stem cell variants contributes to chronic lung conditions.
Details
- Title: Subtitle
- Cloning a profibrotic stem cell variant in idiopathic pulmonary fibrosis
- Creators
- Shan Wang - University of HoustonWei Rao - University of HoustonAshley Hoffman - University of HoustonJennifer Lin - University of HoustonJustin Li - AccuraScience, Johnston, IA 50131, USATao Lin - University of HoustonAudrey-Ann Liew - University of HoustonMatthew Vincent - Nuwa Medical Systems, Houston, TX 77479, USATinne C J Mertens - The University of Texas Health Science Center at HoustonHarry Karmouty-Quintana - The University of Texas Health Science Center at HoustonChristopher P Crum - Brigham and Women's HospitalMark L Metersky - University of ConnecticutDavid A Schwartz - Departments of Medicine and Microbiology and Immunology, University of Colorado School of Medicine, Aurora, CO 80045, USAPeter J A Davies - Czech Academy of Sciences, Institute of BiotechnologyClifford Stephan - Czech Academy of Sciences, Institute of BiotechnologySoma S K Jyothula - Memorial Hermann–Texas Medical CenterAjay Sheshadri - The University of Texas MD Anderson Cancer CenterErik Eddie Suarez - Houston MethodistHoward J Huang - Houston MethodistJohn F Engelhardt - Department of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USABurton F Dickey - The University of Texas MD Anderson Cancer CenterKalpaj R Parekh - University of IowaFrank D McKeon - University of HoustonWa Xian - University of Houston
- Resource Type
- Journal article
- Publication Details
- Science translational medicine, Vol.15(693), eabp9528
- DOI
- 10.1126/scitranslmed.abp9528
- PMID
- 37099633
- PMCID
- PMC10794039
- NLM abbreviation
- Sci Transl Med
- ISSN
- 1946-6234
- eISSN
- 1946-6242
- Grant note
- R01 HL136370 / NHLBI NIH HHS
- Language
- English
- Date published
- 04/26/2023
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Anatomy and Cell Biology; Radiation Oncology; Cardiothoracic Surgery; Internal Medicine
- Record Identifier
- 9984399499802771
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