Combinatorial treatment of acute myocardial infarction using stem cells and their derived exosomes resulted in improved heart performance
Combinatorial treatment of acute myocardial infarction using stem cells and their derived exosomes resulted in improved heart performance
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使用干细胞及其衍生的外泌体联合治疗急性心肌梗死可改善心脏性能。
DOI：
10.1186/s13287-019-1353-3
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发表时间：
2019-10-10
影响因子：
7.5
通讯作者：
Yang, Yuejin
中科院分区：
文献类型：
--
作者：
Huang, Peisen;Wang, Li;Yang, Yuejin
背景：骨髓间充质干细胞（MSC）是用于心脏再生和研究的最常见的细胞类型之一。梗死心脏中递送的间充质干细胞的低存活率和难以保留仍然是该领域的主要挑战。干细胞源性外泌体 (Exo) 的共同递送有望改善移植 MSC 的募集和存活。方法：从 MSC 中分离出 Exo，并在梗死后第 1 天、第 3 天或第 7 天通过心肌内注射（有或没有静脉输注阿托伐他汀预处理的 MSC）将 Exo 递送至急性心肌梗死 (AMI) 大鼠心脏。进行超声心动图评估心脏功能。进行组织学分析和 ELISA 测试来评估梗塞边界区的血管生成、SDF-1 和炎症因子表达。使用流式细胞术和 Hoechst 33342 染色测定评估 Exo 对 MSC 的抗凋亡作用。结果：我们发现，与单独使用 Exo 或 MSC 治疗的对照相比，心肌内递送 Exo，然后将 MSC 移植（简而言之，Exo + MSC 治疗）至 MI 心脏，进一步改善了心脏功能，减少了梗塞面积，并增加了新血管形成。值得注意的是，比较三个联合移植组，AMI后30分钟心肌内注射Exo联合AMI后第3天的MSC移植获得了最高的心功能改善。观察到的心脏功能增强可能是由于 Exo 注射改善了微环境，例如炎症反应减少以及 MSC 招募和保留更好。此外，我们证明，移植前注射 Exo 可增强 MSC 的存活率，并在体外和体内减少其凋亡。结论：以顺序方式组合递送外泌体和干细胞可有效减少 AMI 后的疤痕大小并恢复心脏功能。这种方法可能是基于干细胞的心脏修复和治疗的另一种有前途的策略。
Background: Bone marrow mesenchymal stem cells (MSCs) are among the most common cell types to be used and studied for cardiac regeneration. Low survival rate and difficult retention of delivered MSCs in infarcted heart remain as major challenges in the field. Co-delivery of stem cell-derived exosomes (Exo) is expected to improve the recruitment and survival of transplanted MSCs.Methods: Exo was isolated from MSCs and delivered to an acute myocardial infarction (AMI) rat heart through intramyocardial injection with or without intravenous infusion of atrovastatin-pretreated MSCs on day 1, day 3, or day 7 after infarction. Echocardiography was performed to evaluate cardiac function. Histological analysis and ELISA test were performed to assess angiogenesis, SDF-1, and inflammatory factor expression in the infarct border zone. The anti-apoptosis effect of Exo on MSCs was evaluated using flow cytometry and Hoechst 33342 staining assay.Results: We found that intramyocardial delivery of Exo followed by MSC transplantation (in brief, Exo+MSC treatment) into MI hearts further improved cardiac function, reduced infarct size, and increased neovascularization when compared to controls treated with Exo or MSCs alone. Of note, comparing the three co-transplanting groups, intramyocardially injecting Exo 30 min after AMI combined with MSCs transplantation at day 3 after AMI achieved the highest improvement in heart function. The observed enhanced heart function is likely due to an improved microenvironment via Exo injection, which is exemplified as reduced inflammatory responses and better MSC recruitment and retention. Furthermore, we demonstrated that pre-transplantation injection of Exo enhanced survival of MSCs and reduced their apoptosis both in vitro and in vivo.Conclusions: Combinatorial delivery of exosomes and stem cells in a sequential manner effectively reduces scar size and restores heart function after AMI. This approach may represent as an alternative promising strategy for stem cell-based heart repair and therapy.