Vascular Repair by Tissue-Resident Endothelial Progenitor Cells in Endotoxin-Induced Lung Injury
Vascular Repair by Tissue-Resident Endothelial Progenitor Cells in Endotoxin-Induced Lung Injury
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DOI：
10.1165/rcmb.2014-0185oc
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发表时间：
2015-10-01
影响因子：
6.4
通讯作者：
Tatsumi, Koichiro
中科院分区：
文献类型：
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作者：
Kawasaki, Takeshi;Nishiwaki, Tetsu;Tatsumi, Koichiro
血管破裂是急性呼吸窘迫综合征的病理特征之一。骨髓来源的循环内皮祖细胞（EPCs）和肺组织来源的EPCs在肺血管修复中起着关键作用，但哪一种细胞在局部肺血管发生中占主导地位仍有待明确。因此，我们研究了EPCs参与实验性急性呼吸窘迫综合征肺血管内皮细胞（PVECs）再生过程的起源。研究了来自经气管内施用LPS的小鼠的肺样品的细胞动力学和EPC功能。定量流式细胞术分析表明，PVEC的数量在LPS攻击的第1天减少约20%，然后在第7天恢复。溴脱氧尿苷掺入试验和免疫荧光显微镜显示增殖的PVEC优先位于毛细血管。使用BM嵌合体小鼠的实验显示，大多数再生的PVEC是组织驻留细胞，并且BM衍生的细胞几乎不能作为PVEC移植。循环中推定的表型EPCs的数量在LPS攻击后的第一周内减少。再生的PVECs具有较高的集落形成和血管生成能力、细胞内活性氧清除能力和乙醛脱氢酶活性，以及耐药基因Abcb 1b基因表达增强，表明PVECs群体包括在PVECs再生过程中激活的组织驻留EPCs。增殖期PVEC表面CD 34、Flk-1/KDR和c-kit表达较强，Prom 1/CD 133表达较弱。我们的研究结果表明，肺组织驻留EPCs主要有助于肺血管修复后，内毒素诱导的损伤。
Vascular disruption is one of the pathological hallmarks in acute respiratory distress syndrome. Bone marrow (BM)-derived circulating endothelial progenitor cells (EPCs) and lung tissue-resident EPCs have been considered to play a pivotal role in pulmonary vascular repair; however, which population is predominant in local pulmonary vasculogenesis remains to be clarified. We therefore examined the origin of EPCs participating in the regenerative process of pulmonary vascular endothelial cells (PVECs) in experimental acute respiratory distress syndrome. Lung samples from mice administered LPS intratracheally were investigated for cell dynamics and EPC functions. Quantitative flow cytometric analysis demonstrated that the number of PVECs decreased by roughly 20% on Day 1 and then recovered on Day 7 of LPS challenge. Bromodeoxyuridine-incorporation assays and immunofluorescence microscopy demonstrated that proliferating PVECs preferentially located in the capillary vessels. Experiments using BM chimera mice revealed that most of the regenerating PVECs were tissue-resident cells, and BM-derived cells hardly engrafted as PVECs. The population of circulating putative phenotypical EPCs decreased during the first week after LPS challenge. The regenerating PVECs were characterized by high colony-forming and vasculogenic capacities, intracellular reactive oxygen species scavenging and aldehyde dehydrogenase activites, and enhanced gene expression of Abcb1b (a drug-resistant gene), suggesting that the population of PVECs included tissue-resident EPCs activated during regenerative process of PVECs. The proliferating PVECs expressed CD34, Flk-1/KDR, and c-kit more strongly and Prom1/CD133 less strongly on the surface than nonproliferating PVECs. Our findings indicated that lung tissue-resident EPCs predominantly contribute to pulmonary vascular repair after endotoxin-induced injury.