Sekine Ayumi, Nishiwaki Tetsu, Nishimura Rintaro, Kawasaki Takeshi, Urushibara Takashi, Suda Rika, Suzuki Toshio, Takayanagi Shin, Terada Jiro, Sakao Seiichiro, Tada Yuji, Iwama Atsushi, Tatsumi Koichiro
Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan; and
Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan; and.
Am J Physiol Lung Cell Mol Physiol. 2016 Jun 1;310(11):L1130-42. doi: 10.1152/ajplung.00375.2014. Epub 2016 Apr 8.
Pulmonary vascular endothelial cells could contribute to maintain homeostasis in adult lung vasculature. "Tissue-resident" endothelial progenitor cells (EPCs) play pivotal roles in postnatal vasculogenesis, vascular repair, and tissue regeneration; however, their local pulmonary counterparts remain to be defined. To determine whether prominin-1/CD133 expression can be a marker of tissue-resident vascular EPCs in the pulmonary circulation, we examined the origin and characteristics of prominin-1/CD133-positive (Prom1(+)) PVECs considering cell cycle status, viability, histological distribution, and association with pulmonary vascular remodeling. Prom1(+) PVECs exhibited high steady-state transit through the cell cycle compared with Prom1(-) PVECs and exhibited homeostatic cell division as assessed using the label dilution method and mice expressing green fluorescent protein. In addition, Prom1(+) PVECs showed more marked expression of putative EPC markers and drug resistance genes as well as highly increased activation of aldehyde dehydrogenase compared with Prom1(-) PVECs. Bone marrow reconstitution demonstrated that tissue-resident cells were the source of >98% of Prom1(+) PVECs. Immunofluorescence analyses revealed that Prom1(+) PVECs preferentially resided in the arterial vasculature, including the resistant vessels of the lung. The number of Prom1(+) PVECs was higher in developing postnatal lungs. Sorted Prom1(+) PVECs gave rise to colonies and formed fine vascular networks compared with Prom1(-) PVECs. Moreover, Prom1(+) PVECs increased in the monocrotaline and the Su-5416 + hypoxia experimental models of pulmonary vascular remodeling. Our findings indicated that Prom1(+) PVECs exhibited the phenotype of tissue-resident EPCs. The unique biological characteristics of Prom1(+) PVECs predominantly contribute to neovasculogenesis and maintenance of homeostasis in pulmonary vascular tissues.
肺血管内皮细胞有助于维持成年肺血管系统的稳态。“组织驻留”内皮祖细胞（EPCs）在出生后血管生成、血管修复和组织再生中起关键作用；然而，它们在肺部的局部对应细胞仍有待确定。为了确定prominin-1/CD133的表达是否可以作为肺循环中组织驻留血管EPCs的标志物，我们从细胞周期状态、活力、组织学分布以及与肺血管重塑的关联等方面，研究了prominin-1/CD133阳性（Prom1(+)）肺血管内皮细胞（PVECs）的起源和特征。与Prom1(-) PVECs相比，Prom1(+) PVECs在细胞周期中表现出较高的稳态转换，并通过标记稀释法和表达绿色荧光蛋白的小鼠评估显示出稳态细胞分裂。此外，与Prom1(-) PVECs相比，Prom1(+) PVECs显示出更多明显的假定EPC标志物和耐药基因表达，以及醛脱氢酶的高度激活。骨髓重建表明，组织驻留细胞是>98%的Prom1(+) PVECs的来源。免疫荧光分析显示，Prom1(+) PVECs优先驻留在动脉血管系统中，包括肺的阻力血管。出生后发育中的肺中Prom1(+) PVECs的数量更高。与Prom1(-) PVECs相比，分选的Prom1(+) PVECs能形成集落并形成精细的血管网络。此外，在野百合碱和Su-5416 + 缺氧肺血管重塑实验模型中，Prom1(+) PVECs数量增加。我们的研究结果表明，Prom1(+) PVECs表现出组织驻留EPCs的表型。Prom1(+) PVECs独特的生物学特性主要有助于肺血管组织中的新生血管生成和稳态维持。
