| Autor: |
Wang, Shan, Rao, Wei, Hoffman, Ashley, Lin, Jennifer, Li, Justin, Lin, Tao, Liew, Audrey-Ann, Vincent, Matthew, Mertens, Tinne C. J., Karmouty-Quintana, Harry, Crum, Christopher P., Metersky, Mark L., Schwartz, David A., Davies, Peter J. A., Stephan, Clifford, Jyothula, Soma S. K., Sheshadri, Ajay, Suarez, Erik Eddie, Huang, Howard J., Engelhardt, John F. |
| Předmět: |
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| Zdroj: |
Science Translational Medicine; 4/26/2023, Vol. 15 Issue 693, p1-15, 15p |
| Abstrakt: |
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. Seeing stem cell variants: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease characterized in part by epithelial cell expression of genes associated with immature basal cells. Here, Wang and colleagues used single-cell cloning technologies to generate libraries of basal stem cells from IPF and control lungs. They identified a basal stem cell variant that could transform lung fibroblasts into myofibroblasts and was sensitive to inhibitors of epidermal growth factor and mammalian target of rapamycin signaling in vitro. In mice, xenografts of these cells were able to recruit myofibroblasts. This variant was different from profibrotic stem cell variants identified in chronic obstructive lung disease and was present at very low percentages in normal lungs, suggesting that inappropriate accrual of this stem cell variant might contribute to IPF. —MN [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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