Biological significance of endothelial stem cells in the preexisting blood vessels

 

Nobuyuki Takakura

Research Institute for Microbial Diseases, The University of Osaka

 

Recently, it has become increasingly clear that aging-induced declines in capillary density and function are associated with dementia, osteoporosis, and deterioration of skeletal muscle and visceral organ function. Thus, understanding capillary degradation due to aging has emerged as an important research theme in the context of an aging society. The lumen of blood vessels is lined by a single layer of endothelial cells, which are structurally stabilized by mural cells (especially pericytes in capillaries) adhering from the basement membrane side. This structure suppresses the motility of endothelial cells, and most of them remain in a quiescent state. Although vascular endothelial cells may seem to exist in a long-term stable state, it has now been revealed that they decrease due to systemic inflammation observed with aging. In our in vivo experimental model, which accelerates aging, we have demonstrated that elevated TNF-α expression from intestinal macrophages—triggered by the gut microbiota—induces capillary damage in intestinal villi. This inflammatory response further spreads to the adjacent liver, leading to disruption of the liver sinusoidal vasculature. We have clarified this sequential damage pathway. The propagation of TNF-α expression is believed to eventually affect distant organs and ultimately contribute to sarcopenia. Suppressing inflammation-induced capillary breakdown is undoubtedly crucial for preventing age-related decline in organ function and aging-associated diseases. We have long advocated the importance of developing drugs (or food-derived substances) that activate Tie2—a receptor-type tyrosine kinase expressed in vascular endothelial cells that contributes to vascular structural stabilization. On the other hand, in organs where capillaries have already collapsed and lost function, regeneration of the capillary network becomes necessary. Through our analyses, we have discovered that existing blood vessels contain vascular endothelial stem cells capable of inducing vascular regeneration. We have elucidated that these cells play a key role in maintaining vascular homeostasis within the body. In this lecture, I will introduce new insights into vascular development, aging, organ specificity, and functional homeostasis that have emerged through our studies of these vascular endothelial stem cells.

 

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