Brexogen Research Center, Brexogen Inc., Songpa‑gu, Seoul, 05855, South Korea.
Department of Biomedicine & Health Sciences, The Catholic University of Korea, 222 Banpo-daero, Seoho-gu, Seoul, 06591, Republic of Korea.
J Nanobiotechnology. 2024 Apr 4;22(1):149. doi: 10.1186/s12951-024-02410-x.
Myocardial infarction (MI), a representative form of ischemic heart disease, remains a huge burden worldwide. This study aimed to explore whether extracellular vesicles (EVs) secreted from hyaluronic acid (HA)-primed induced mesenchymal stem cells (HA-iMSC-EVs) could enhance the cardiac repair after MI.
HA-iMSC-EVs showed typical characteristics for EVs such as morphology, size, and marker proteins expression. Compared with iMSC-EVs, HA-iMSC-EVs showed enhanced tube formation and survival against oxidative stress in endothelial cells, while reduced reactive oxygen species (ROS) generation in cardiomyocytes. In THP-1 macrophages, both types of EVs markedly reduced the expression of pro-inflammatory signaling players, whereas HA-iMSC-EVs were more potent in augmenting anti-inflammatory markers. A significant decrease of inflammasome proteins was observed in HA-iMSC-EV-treated THP-1. Further, phospho-SMAD2 as well as fibrosis markers in TGF-β1-stimulated cardiomyocytes were reduced in HA-iMSC-EVs treatment. Proteomic data showed that HA-iMSC-EVs were enriched with multiple pathways including immunity, extracellular matrix organization, angiogenesis, and cell cycle. The localization of HA-iMSC-EVs in myocardium was confirmed after delivery by either intravenous or intramyocardial route, with the latter increased intensity. Echocardiography revealed that intramyocardial HA-iMSC-EVs injections improved cardiac function and reduced adverse cardiac remodeling and necrotic size in MI heart. Histologically, MI hearts receiving HA-iMSC-EVs had increased capillary density and viable myocardium, while showed reduced fibrosis.
Our results suggest that HA-iMSC-EVs improve cardiac function by augmenting vessel growth, while reducing ROS generation, inflammation, and fibrosis in MI heart.
心肌梗死（MI）是缺血性心脏病的代表性形式，在全球范围内仍是一个巨大的负担。本研究旨在探讨透明质酸（HA）预刺激诱导间充质干细胞（HA-iMSC-EVs）分泌的细胞外囊泡（EVs）是否能增强 MI 后的心脏修复。
HA-iMSC-EVs 表现出 EVs 的典型特征，如形态、大小和标记蛋白表达。与 iMSC-EVs 相比，HA-iMSC-EVs 表现出增强的内皮细胞管状形成和对氧化应激的生存能力，而在心肌细胞中减少活性氧（ROS）的产生。在 THP-1 巨噬细胞中，两种类型的 EVs 均显著降低促炎信号分子的表达，而 HA-iMSC-EVs 则更能增强抗炎标志物的表达。在 HA-iMSC-EV 处理的 THP-1 中，炎症小体蛋白的表达明显减少。此外，在 TGF-β1 刺激的心肌细胞中，磷酸化 SMAD2 以及纤维化标志物的表达也减少。蛋白质组学数据显示，HA-iMSC-EVs 富含多个通路，包括免疫、细胞外基质组织、血管生成和细胞周期。通过静脉或心肌内途径给药后，在心肌中证实了 HA-iMSC-EVs 的定位，后者的强度增加。超声心动图显示，心肌内注射 HA-iMSC-EVs 可改善心脏功能，减少 MI 心脏的不良心脏重构和坏死面积。组织学上，接受 HA-iMSC-EVs 的 MI 心脏增加了毛细血管密度和存活心肌，同时减少了纤维化。
我们的结果表明，HA-iMSC-EVs 通过增强血管生长，同时减少 MI 心脏中的 ROS 生成、炎症和纤维化，改善心脏功能。
