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

Abstract

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.