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滋养层干细胞来源的外泌体通过调节let-7i/YAP通路改善阿霉素诱导的扩张型心肌病。

Trophoblast Stem-Cell-Derived Exosomes Improve Doxorubicin-Induced Dilated Cardiomyopathy by Modulating the let-7i/YAP Pathway.

作者信息

Ni Jie, Liu Yihai, Wang Kun, Wu Mingyue, Kang Lina, Sha Dujuan, Xu Biao, Gu Rong

机构信息

Department of Cardiology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing 21008, P.R. China.

Department of General Medicine, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing 210008, P.R. China.

出版信息

Mol Ther Nucleic Acids. 2020 Oct 15;22:948-956. doi: 10.1016/j.omtn.2020.10.014. eCollection 2020 Dec 4.

DOI:10.1016/j.omtn.2020.10.014
PMID:33294288
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7680701/
Abstract

Trophoblast stem cells (TSCs) have been confirmed to play a cardioprotective role in heart failure. However, whether TSC-derived exosomes (TSC-exos) can protect against cardiac injury remains unclear. In the present study, TSC-exos were isolated from the supernatant of TSCs using the ultracentrifugation method and characterized by transmission electron microscopy and western blotting. Utilizing the public Gene Expression Omnibus (GEO) database, we found that let-7i and Yes-associated protein 1 (YAP) could participate in the development of heart failure. , AC16 cardiomyocytes subjected to doxorubicin (DOX) were treated with TSC-exos or let-7i mimic. Flow cytometry showed that TSC-exos and let-7i both decreased cardiomyocyte apoptosis. , mice that were intraperitoneally injected into DOX received either PBS, TSC-exos, or AAV9-let7i for let-7i overexpression. Mice receiving TSC-exos and AAV9-let7i showed improved cardiac function and decreased inflammatory responses, accompanied by downregulated YAP signaling. Mechanistically, TSC-exos could transfer let-7i to cardiomyocytes and silence the YAP signaling pathway. In conclusion, TSC-exos could alleviate DOX-induced cardiac injury via the let-7i/YAP pathway, which sheds new light on the application of TSC-exos as a potential therapeutic tool for heart failure.

摘要

滋养层干细胞（TSCs）已被证实在心衰中发挥心脏保护作用。然而，TSC来源的外泌体（TSC-exos）是否能预防心脏损伤仍不清楚。在本研究中，采用超速离心法从TSCs的上清液中分离出TSC-exos，并通过透射电子显微镜和蛋白质免疫印迹法进行表征。利用公共基因表达综合数据库（GEO），我们发现let-7i和Yes相关蛋白1（YAP）可能参与心衰的发展。用TSC-exos或let-7i模拟物处理阿霉素（DOX）处理的AC16心肌细胞。流式细胞术显示TSC-exos和let-7i均降低了心肌细胞凋亡。给腹腔注射DOX的小鼠分别注射PBS、TSC-exos或用于let-7i过表达的腺相关病毒9（AAV9）-let7i。接受TSC-exos和AAV9-let7i的小鼠心脏功能改善，炎症反应降低，同时YAP信号下调。机制上，TSC-exos可以将let-7i转移到心肌细胞并使YAP信号通路沉默。总之，TSC-exos可通过let-7i/YAP途径减轻DOX诱导的心脏损伤，这为TSC-exos作为心衰潜在治疗工具的应用提供了新的思路。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1554/7680701/594ab668685e/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1554/7680701/e03e728538a1/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1554/7680701/d96f0f4aa144/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1554/7680701/956075778fdd/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1554/7680701/37bfba520641/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1554/7680701/02ece0357b24/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1554/7680701/b58794a8d8e5/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1554/7680701/594ab668685e/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1554/7680701/e03e728538a1/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1554/7680701/d96f0f4aa144/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1554/7680701/956075778fdd/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1554/7680701/37bfba520641/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1554/7680701/02ece0357b24/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1554/7680701/b58794a8d8e5/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1554/7680701/594ab668685e/gr6.jpg

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