2023-05-17 ヒューストン大学(UH)
◆IPFは進行性で不可逆的な肺疾患であり、肺が瘢痕化し呼吸が困難になります。研究チームは、IPF患者と非患者の肺組織を用いて単一細胞クローニング技術を使用し、特に病原的な幹細胞変異体を同定しました。これらの変異細胞は、瘢痕組織形成を促進する特性を持ち、将来的な治療の標的となる可能性があります。
◆研究結果は、特発性肺線維症の理解と治療の進展に貢献するものであり、他の肺疾患とは異なる特異な変異細胞が関与していることが示されています。
<関連情報>
- https://uh.edu/news-events/stories/2023/may-2023/05172023-mckeon-xian-lungs-fibrosis-cells.php
- https://www.science.org/doi/10.1126/scitranslmed.abp9528
特発性肺線維症におけるプロフィブロティック幹細胞バリアントのクローニング Cloning a profibrotic stem cell variant in idiopathic pulmonary fibrosis
Shan Wang,Wei Rao,Ashley Hoffman,Jennifer Lin,Justin Li,Tao Lin,Audrey-Ann Liew,Matthew Vincent,Tinne C. J. Mertens,Harry Karmouty-Quintana,Christopher P. Crum,Mark L. Metersky,David A. Schwartz,Peter J. A. Davies,Clifford Stephan,Soma S. K. Jyothula,Ajay Sheshadri,Erik Eddie Suarez,Howard J. Huang,John F. Engelhardt,Burton F. Dickey ,Kalpaj R. Parekh,Frank D. McKeon and Wa Xian
Science Translational Medicine Published:26 Apr 2023
DOi:https://doi.org/10.1126/scitranslmed.abp9528
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.
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
