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 6

Angiodiversity in the lung microvascular capillary bed, localization of MVPCs, and impact of Tsc2KD in MVPCs at the single-cell level.

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Angiodiversity in the lung microvascular capillary bed, localization of ...
Adult WT or Tsc2KD mice were induced with tamoxifen; 2 days or 10 weeks later, lungs were collected and digested to form single-cell suspensions, and samples were pooled and sequenced (WT: day 2, n = 5; 10 weeks, n = 4; Tsc2KD: day 2, n = 4; 10 weeks, n = 4). (A and B) Uniform manifold approximation and projection (UMAP) with Seurat clustering of single-cell lung suspensions in Loupe Browser 5.0 (10x Genomics) was annotated to define lung MVEC clusters as general capillary (Gcap) or Car4hi/aerocytes (Acap). Common cluster designations (0 to 27) are presented. (C) Differential expression of Tsc2KD versus WT MVEC clusters at 2 days and 10 weeks. (D and E) DEGs detected in a comparison of Tsc2KD versus WT at 10 weeks using Seurat FindMarkers were used with a cutoff of adjusted P value less than 0.05 and log fold change of at least 1. A custom list of genes important for vascular function was selected from the DEG list. Heatmap was generated using the dittoHeatmap function from the dittoSeq package (Bioconductor). Expression of vascular (D) and mesenchymal stem cell–related (E) markers in WT and TSC2KD at 10 weeks. (F and G) Loupe Browser v5 was used to define the heterogeneity in the general capillary bed via dot plot and heatmap of known microvascular endothelial genes. (H and I) Abcg2 expression (H) or coexpression (I) of vascular endothelial stem cell (VESC) markers at 10 weeks in WT or Tsc2KD dot plot. Five to eight mice per group were pooled for these experiments.