Department of Cardiology, Second Affiliated Hospital, College of Medicine, Zhejiang University, 88 Jiefang Rd, Hangzhou, 310009, Zhejiang Province, People's Republic of China.
Cardiovascular Key Laboratory of Zhejiang Province, 88 Jiefang Rd, Hangzhou, 310009, Zhejiang Province, People's Republic of China.
Stem Cell Res Ther. 2020 Jul 8;11(1):273. doi: 10.1186/s13287-020-01782-9.
Age and other cardiovascular risk factors have been reported to impair the activities of mesenchymal stem cells (MSCs), which will affect the efficacy of stem cell transplantation. The objective of the study is to investigate whether exosomes derived from human umbilical cord MSCs (UMSCs) could enhance the activities of bone marrow MSCs from old person (OMSCs), and improve their capacity for cardiac repair.
Exosomes extracted from conditioned medium of UMSCs were used to treat OMSCs to generate OMSCs. The key molecule in the exosomes that have potential to rejuvenate aged MSCs were screened, and the role of OMSC was tested in the mouse model of mycardial infarction (MI).
We found the activity of senescence-associated β-galactosidase and the expression of aging-related factors such as p53, p21, and p16 were significantly higher in OMSCs than those in UMSCs. After treatment with UMSC exosomes, these senescence phenotypes of OMSCs were remarkably reduced. The proliferation, migration, differentiation, and anti-apoptotic and paracrine effect were increased in OMSCs. In vivo study, mice with cardiac infarction had significantly better cardiac function, less fibrosis, and more angiogenesis after they were injected with OMSCs as compared with those with OMSC. There was more miR-136 expression in UMSCs and OMSCs than in OMSCs. Upregulation of miR-136 by transfection of miR-136 mimic into OMSCs significantly attenuated the apoptosis and senescence of OMSCs. Apoptotic peptidase activating factor (Apaf1) was found to be the downstream gene that is negatively regulated by miR-136 via directly targeting at its 3'UTR.
Our data suggest that exosomes from young MSCs can improve activities of aged MSCs and enhance their function for myocardial repair by transferring exosomal miR-136 and downregulating Apaf1.
年龄和其他心血管危险因素已被报道会损害间充质干细胞（MSCs）的活性，这将影响干细胞移植的疗效。本研究旨在探讨人脐带间充质干细胞（UMSC）来源的外泌体是否能增强老年人骨髓间充质干细胞（OMSC）的活性，提高其心脏修复能力。
用 UMSC 条件培养基提取的外泌体处理 OMSC 以生成 OMSC。筛选出有潜力使衰老 MSC 年轻化的外泌体中的关键分子，并在心肌梗死（MI）小鼠模型中测试 OMSC 的作用。
我们发现 OMSC 的衰老相关β-半乳糖苷酶活性和衰老相关因子（如 p53、p21 和 p16）的表达明显高于 UMSC。用 UMSC 外泌体处理后，这些 OMSC 的衰老表型显著减少。OMSC 的增殖、迁移、分化、抗凋亡和旁分泌作用增强。体内研究发现，与 OMSC 相比，注射 OMSC 的心肌梗死小鼠的心脏功能明显改善，纤维化减少，血管生成增加。与 OMSC 相比，UMSC 和 OMSC 中的 miR-136 表达更高。转染 miR-136 模拟物上调 OMSC 中的 miR-136 可显著减轻 OMSC 的凋亡和衰老。凋亡蛋白酶激活因子（Apaf1）被发现是 miR-136 通过直接靶向其 3'UTR 负调控的下游基因。
我们的数据表明，年轻 MSCs 的外泌体可以通过转移外泌体 miR-136 和下调 Apaf1 来改善衰老 MSCs 的活性，增强其心肌修复功能。
