Department of Critical Care Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, No. 160, Pujian Road, Pudong New District, Shanghai, 200120, China.
Cell Commun Signal. 2023 Aug 16;21(1):205. doi: 10.1186/s12964-023-01229-7.
Endothelial glycocalyx (EG) is an active player and treatment target in inflammatory-related vascular leakage. The bone marrow mesenchymal stem cells (bMSCs) are promising potential treatments for leakage; however, the therapeutic effect and mechanism of bMSC on EG degradation needs to be elucidated.
EG degradation and leakage were evaluated in both lipopolysaccharide (LPS)-induced mice ear vascular leakage model and LPS-stimulated human umbilical vein endothelial cells (HUVECs) model treated with bMSCs. Extracellular vesicles (EVs) were extracted from bMSCs and the containing microRNA profile was analyzed. EV and miR let-7-5p were inhibited to determine their function in the therapeutic process. The ABL2 gene was knockdown in HUVECs to verify its role as a therapeutic target in EG degradation.
bMSCs treatment could alleviate LPS-induced EG degradation and leakage in vivo and in vitro, whereas EVs/let-7-5p-deficient bMSCs were insufficient to reduce EG degradation. LPS down-regulated the expression of let-7-5p while upregulated endothelial expression of ABL2 in HUVECs and induced EG degradation and leakage. bMSC-EVs uptaken by HUVECs could deliver let-7-5p targeting endothelial ABL2, which suppressed the activation of downstream p38MAPK and IL-6, IL-1β levels, and thus reversed LPS-induced EG degradation and leakage.
bMCSs alleviate LPS-induced EG degradation and leakage through EV delivery of miR let-7-5p targeting endothelial ABL2.
内皮糖萼（EG）是炎症相关血管渗漏的一个活跃参与者和治疗靶点。骨髓间充质干细胞（bMSCs）是一种很有前途的潜在治疗渗漏的方法；然而，bMSC 对 EG 降解的治疗效果和机制仍需阐明。
在脂多糖（LPS）诱导的小鼠耳部血管渗漏模型和 LPS 刺激的人脐静脉内皮细胞（HUVECs）模型中，评估 EG 降解和渗漏情况，bMSCs 处理后提取细胞外囊泡（EVs）并分析其含有的 microRNA 谱。抑制 EV 和 miR let-7-5p 以确定它们在治疗过程中的功能。在 HUVECs 中敲低 ABL2 基因，以验证其作为 EG 降解治疗靶点的作用。
bMSCs 治疗可减轻 LPS 诱导的体内和体外 EG 降解和渗漏，而 EV/let-7-5p 缺陷的 bMSCs 则不足以减少 EG 降解。LPS 下调了 HUVECs 中 let-7-5p 的表达，而上调了内皮 ABL2 的表达，从而诱导 EG 降解和渗漏。LPS 诱导的 EG 降解和渗漏可通过 HUVECs 摄取 bMSC-EVs 来传递 miR let-7-5p 靶向内皮 ABL2，从而抑制下游 p38MAPK 和 IL-6、IL-1β 水平的激活，逆转 LPS 诱导的 EG 降解和渗漏。
bMSCs 通过 EV 传递 miR let-7-5p 靶向内皮 ABL2 减轻 LPS 诱导的 EG 降解和渗漏。
