Reactivation and dysregulation of the mTOR signaling pathway is a hallmark of aging and chronic lung disease, however the impact on microvascular progenitor cells (MVPC), 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 MVPC 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, disruption of p53 and Wnt pathways, with consequent loss of alveolar-capillary structure and function. Following mTOR activation these MVPC 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, microvascular niche homeostasis as well as a cell-based mechanism driving loss of tissue structure underlying lung aging and the development of emphysema.

中文翻译：

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成人肺微血管祖细胞中 mTOR 信号的激活会加速肺衰老。

mTOR 信号通路的重新激活和失调是衰老和慢性肺病的标志，但其对微血管祖细胞 (MVPC)、毛细血管抑制和组织稳态的影响尚不清楚。虽然长期以来一直假设成年肺血管祖细胞的存在，但这些研究表明，通过功能、谱系和转录组分析，Abcg2 丰富了成年小鼠和人类肺部中存在的血管生成组织驻留 MVPC 群体。这些研究将人和小鼠 MVPC 特异性 mTORC1 激活与干细胞干性降低、血管生成潜力、p53 和 Wnt 通路破坏以及随之而来的肺泡毛细血管结构和功能丧失联系起来。mTOR 激活后，这些 MVPC 适应独特的转录组特征，并作为血管多样性微血管内皮亚群中的静脉亚群出现。因此，我们的研究结果支持 mTOR 在维持 MVPC 功能、微血管生态位稳态以及导致肺衰老和肺气肿发展的组织结构丧失的细胞机制中发挥重要作用。