Wang Renjie, Liu Lulu, Han Fusheng, Ma Qian, He Hua
Cardiac Division of Emergency Intensive Care Unit, Beijing Anzhen Hospital, Capital Medical University, Anzhen Road Second, Chaoyang District, Beijing, 100029, People's Republic of China.
Cardiac Division of Emergency Intensive Care Unit, Beijing Anzhen Hospital, Capital Medical University, Anzhen Road Second, Chaoyang District, Beijing, 100029, People's Republic of China.
Biochem Biophys Res Commun. 2025 Jul 1;768:151920. doi: 10.1016/j.bbrc.2025.151920. Epub 2025 Apr 30.
Acute myocardial infarction (AMI) is the most common ischemic heart disease with high morbidity and high mortality. Although the treatment of AMI is constantly developing, ischemia-reperfusion (I/R) injury remains a complex problem. In recent years, human umbilical cord-derived mesenchymal stem cell-derived exosomes (hUC-MSC-EXO) have been shown to alleviate related damages. However, the long-term effects, safety, and mechanism of action have not yet been fully explored.
We constructed human umbilical cord-derived mesenchymal stem cell-derived engineered exosomes. We compared the short-term and long-term protective abilities of engineered exosomes on myocardium during I/R in cardiomyocytes and rat models, and determined their long-term safety. At the same time, key pathways and genes were predicted through exosome sequencing.
hUC-MSC-EXO significantly reduced apoptosis, oxidative stress, and inflammation in both in vitro and in vivo models. In I/R rats, IMTP-EXO demonstrated superior cardioprotective effects, reducing myocardial fibrosis and improving left ventricular function compared to controls. Long-term studies showed enhanced ejection fraction (EF) and fractional shortening (FS) and reduced left ventricular end-diastolic dimensions (LVEDD). Fluorescence imaging revealed higher exosome accumulation in ischemic hearts. Genes related to cardiovascular diseases were obtained through cross-comparison of multiple databases. GO analysis revealed that protein binding was the most highly enriched term. KEGG analysis showed that these genes were primarily involved in apoptosis and the PI3K-Akt signaling pathways. The PPI network showed that TP53, TLR4, EGFR, MAPK3, and GJA1 are central genes of heart I/R injury. GJA1, HMGB1, and PTEN are considered to be key genes by comparing to the comparative toxicogenomic database (CTD).
This study demonstrates that hUC-MSC-derived exosomes, especially IMTP-EXO, are safe, feasible, and effective for reversing ventricular remodeling and improving cardiac function in rat MI models. GJA1, HMGB1, and PTEN may be the key genes associated with myocardial I/R injury. These findings provide critical insights for translating hUC-MSC-EXO into clinical applications for treating myocardial I/R injuries.
急性心肌梗死（AMI）是最常见的缺血性心脏病，发病率和死亡率都很高。尽管AMI的治疗在不断发展，但缺血再灌注（I/R）损伤仍然是一个复杂的问题。近年来，人脐带间充质干细胞来源的外泌体（hUC-MSC-EXO）已被证明可减轻相关损伤。然而，其长期效果、安全性和作用机制尚未得到充分探索。
我们构建了人脐带间充质干细胞来源的工程化外泌体。我们比较了工程化外泌体在心肌细胞和大鼠模型的I/R过程中对心肌的短期和长期保护能力，并确定了它们的长期安全性。同时，通过外泌体测序预测关键途径和基因。
hUC-MSC-EXO在体外和体内模型中均显著降低了细胞凋亡、氧化应激和炎症。在I/R大鼠中，与对照组相比，IMTP-EXO表现出卓越的心脏保护作用，减少了心肌纤维化并改善了左心室功能。长期研究显示射血分数（EF）和缩短分数（FS）增加，左心室舒张末期内径（LVEDD）减小。荧光成像显示缺血心脏中外泌体的积累更高。通过多个数据库的交叉比较获得了与心血管疾病相关的基因。基因本体（GO）分析显示蛋白质结合是最富集的术语。京都基因与基因组百科全书（KEGG）分析表明这些基因主要参与细胞凋亡和PI3K-Akt信号通路。蛋白质-蛋白质相互作用（PPI）网络显示TP53、TLR4、EGFR、MAPK3和GJA1是心脏I/R损伤的核心基因。与比较毒理基因组学数据库（CTD）比较后，GJA1、HMGB1和PTEN被认为是关键基因。
本研究表明，hUC-MSC来源的外泌体，尤其是IMTP-EXO，在大鼠心肌梗死模型中对于逆转心室重构和改善心脏功能是安全、可行且有效的。GJA1、HMGB1和PTEN可能是与心肌I/R损伤相关的关键基因。这些发现为将hUC-MSC-EXO转化为治疗心肌I/R损伤的临床应用提供了重要见解。
