Activation of mTOR signaling in adult lung microvascular progenitor cells accelerates lung aging
Emma C. Mason, … , Fabienne Gally, Susan M. Majka
Emma C. Mason, … , Fabienne Gally, Susan M. Majka
Published October 24, 2023
Citation Information: J Clin Invest. 2023;133(24):e171430. https://doi.org/10.1172/JCI171430.
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Research Article Vascular biology

Activation of mTOR signaling in adult lung microvascular progenitor cells accelerates lung aging

Abstract

Reactivation and dysregulation of the mTOR signaling pathway are a hallmark of aging and chronic lung disease; however, the impact on microvascular progenitor cells (MVPCs), capillary angiostasis, and tissue homeostasis is unknown. While the existence of an adult lung vascular progenitor has long been hypothesized, these studies show that Abcg2 enriches for a population of angiogenic tissue-resident MVPCs present in both adult mouse and human lungs using functional, lineage, and transcriptomic analyses. These studies link human and mouse MVPC-specific mTORC1 activation to decreased stemness, angiogenic potential, and disruption of p53 and Wnt pathways, with consequent loss of alveolar-capillary structure and function. Following mTOR activation, these MVPCs adapt a unique transcriptome signature and emerge as a venous subpopulation in the angiodiverse microvascular endothelial subclusters. Thus, our findings support a significant role for mTOR in the maintenance of MVPC function and microvascular niche homeostasis as well as a cell-based mechanism driving loss of tissue structure underlying lung aging and the development of emphysema.

Authors

Emma C. Mason, Swapna Menon, Benjamin R. Schneider, Christa F. Gaskill, Maggie M. Dawson, Camille M. Moore, Laura Craig Armstrong, Okyong Cho, Bradley W. Richmond, Jonathan A. Kropski, James D. West, Patrick Geraghty, Brigitte N. Gomperts, Kevin C. Ess, Fabienne Gally, Susan M. Majka

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Figure 2

mTOR-activated human lung MVPCs demonstrate similarities to fetal MVPC gene signature and activation of developmental signaling pathways.

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mTOR-activated human lung MVPCs demonstrate similarities to fetal MVPC g...
(A) Array analysis was performed using Affymetrix Human Gene 1.0 ST chips to compare human lung MVPCs isolated from explanted patient lungs or fetal lung fibroblast cultures: normal (3–4 independent patient primary cell lines, 2 female, 2 male, age 60–67), mTOR+ (1 patient, 3 independent cell lines, age 63 years), and fetal (HFL; 3 independent patient primary cell lines, 17–20 weeks of gestation, 2 male, 1 female) MVPCs. Differential expression analysis was carried out using Bioconductor (v3.2, R 3.2.2). A minimal fold change of 1.7, up or down, and P < 0.05 were used as criteria for defining differentially expressed genes. Expression values for these genes are represented in a heatmap. (B) Venn diagram of differentially expressed genes (DEGs) from fetal or mTOR+ MVPCs relative to control. (C) Reverse transcriptase PCR analysis was performed using equal amounts of cDNA from independent MVPC lines to validate the array findings. Each patient sample was analyzed in triplicate, standardized to GAPDH, and normalized to control presented in lane 1 set to 1. Control, blue; fetal, gray; mTOR+ samples, red. n= 3–4, 3, 3. Asterisks represent P values comparing adult with mTOR+ MVPCs. Data were analyzed by nonparametric Wilcoxon/Kruskal-Wallis test and a χ2 approximation and are presented as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001. (D and E) KEGG (D) and Reactome (E) analyses. Dot plot showing significantly enriched pathways and Reactome functional categories in DEG lists from mTOR+ versus control. The color scale represents the adjusted P values obtained for the enrichment of the category in each gene list.