Aging impairs the ability of vascular endothelial stem cells to generate endothelial cells in mice

IF 9.2 1区医学 Q1 PERIPHERAL VASCULAR DISEASE

Angiogenesis Pub Date : 2023-08-10 DOI:10.1007/s10456-023-09891-8

Shota Shimizu, Tomohiro Iba, Hisamichi Naito, Fitriana Nur Rahmawati, Hirotaka Konishi, Weizhen Jia, Fumitaka Muramatsu, Nobuyuki Takakura

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Abstract

Tissue-resident vascular endothelial stem cells (VESCs), marked by expression of CD157, possess long-term repopulating potential and contribute to vascular regeneration and homeostasis in mice. Stem cell exhaustion is regarded as one of the hallmarks of aging and is being extensively studied in several types of tissue-resident stem cells; however, how aging affects VESCs has not been clarified yet. In the present study, we isolated VESCs from young and aged mice to compare their potential to differentiate into endothelial cells in vitro and in vivo. Here, we report that the number of liver endothelial cells (ECs) including VESCs was lower in aged (27–28 month-old) than young (2–3 month-old) mice. In vitro culture of primary VESCs revealed that the potential to generate ECs is impaired in aged VESCs isolated from liver and lung relative to young VESCs. Orthotopic transplantation of VESCs showed that aged VESCs and their progeny expand less efficiently than their young counterparts when transplanted into aged mice, but they are equally functional in young recipients. Gene expression analysis indicated that inflammatory signaling was more activated in aged ECs including VESCs. Using single-cell RNA sequencing data from the Tabula Muris Consortium, we show that T cells and monocyte/macrophage lineage cells including Kupffer cells are enriched in the aged liver. These immune cells produce IL-1β and several chemokines, suggesting the possible involvement of age-associated inflammation in the functional decline of VESCs with age.

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衰老损害了小鼠血管内皮干细胞产生内皮细胞的能力。

以CD157表达为标志的组织驻留血管内皮干细胞（VESCs）具有长期的再增殖潜力，有助于小鼠的血管再生和稳态。干细胞耗竭被认为是衰老的标志之一，并且正在几种类型的组织固有干细胞中进行广泛研究；然而，衰老对VESC的影响还没有明确。在本研究中，我们从年轻和老年小鼠中分离出VESCs，以比较它们在体外和体内分化为内皮细胞的潜力。在这里，我们报道了老年（27-28个月大）小鼠的肝内皮细胞（EC）（包括VESCs）的数量低于年轻（2-3个月大的）小鼠。原代VESCs的体外培养显示，与年轻的VESCs相比，从肝脏和肺部分离的老年VESCs产生EC的潜力受损。VESCs的原位移植表明，当移植到老年小鼠中时，老年VESCs及其后代的扩增效率不如年轻的VESCs，但它们在年轻受体中的功能相同。基因表达分析表明，包括VESCs在内的老年内皮细胞中炎症信号传导更为活跃。使用Tabula Muris Consortium的单细胞RNA测序数据，我们发现T细胞和单核细胞/巨噬细胞谱系细胞（包括库普弗细胞）在衰老的肝脏中富集。这些免疫细胞产生IL-1β和几种趋化因子，表明年龄相关炎症可能参与了VESCs随年龄的功能下降。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Angiogenesis PERIPHERAL VASCULAR DISEASE-

CiteScore

21.90

自引率

8.20%

发文量

审稿时长

6-12 weeks

期刊介绍： Angiogenesis, a renowned international journal, seeks to publish high-quality original articles and reviews on the cellular and molecular mechanisms governing angiogenesis in both normal and pathological conditions. By serving as a primary platform for swift communication within the field of angiogenesis research, this multidisciplinary journal showcases pioneering experimental studies utilizing molecular techniques, in vitro methods, animal models, and clinical investigations into angiogenic diseases. Furthermore, Angiogenesis sheds light on cutting-edge therapeutic strategies for promoting or inhibiting angiogenesis, while also highlighting fresh markers and techniques for disease diagnosis and prognosis.