{"title":"用于治疗心脏纤维化的成人心肌细胞衍生 EVs。","authors":"Marta Prieto-Vila, Yusuke Yoshioka, Naoya Kuriyama, Akihiko Okamura, Yusuke Yamamoto, Asao Muranaka, Takahiro Ochiya","doi":"10.1002/jev2.12461","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <p>Cardiac fibrosis is a common pathological feature of cardiovascular diseases that arises from the hyperactivation of fibroblasts and excessive extracellular matrix (ECM) deposition, leading to impaired cardiac function and potentially heart failure or arrhythmia. Extracellular vesicles (EVs) released by cardiomyocytes (CMs) regulate various physiological functions essential for myocardial homeostasis, which are disrupted in cardiac disease. Therefore, healthy CM-derived EVs represent a promising cell-free therapy for the treatment of cardiac fibrosis.</p>\n </section>\n \n <section>\n \n <p>To this end, we optimized the culture conditions of human adult CMs to obtain a large yield of EVs without compromising cellular integrity by using a defined combination of small molecules. EVs were isolated by ultracentrifugation, and their characteristics were analysed. Finally, their effect on fibrosis was tested.</p>\n </section>\n \n <section>\n \n <p>Treatment of TGFβ-activated human cardiac fibroblasts with EVs derived from CMs using our culture system resulted in a decrease in fibroblast activation markers and ECM accumulation. The rescued phenotype was associated with specific EV cargo, including multiple myocyte-specific and antifibrotic microRNAs, although their effect individually was not as effective as the EV treatment. Notably, pathway analysis showed that EV treatment reverted the transcription of activated fibroblasts and decreased several signalling pathways, including MAPK, mTOR, JAK/STAT, TGFβ, and PI3K/Akt, all of which are involved in fibrosis development. Intracardiac injection of CM-derived EVs in an animal model of cardiac fibrosis reduced fibrotic area and increased angiogenesis, which correlated with improved cardiac function.</p>\n </section>\n \n <section>\n \n <p>These findings suggest that EVs derived from human adult CMs may offer a targeted and effective treatment for cardiac fibrosis, owing to their antifibrotic properties and the specificity of cargo.</p>\n </section>\n </div>","PeriodicalId":15811,"journal":{"name":"Journal of Extracellular Vesicles","volume":null,"pages":null},"PeriodicalIF":15.5000,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11211925/pdf/","citationCount":"0","resultStr":"{\"title\":\"Adult cardiomyocytes-derived EVs for the treatment of cardiac fibrosis\",\"authors\":\"Marta Prieto-Vila, Yusuke Yoshioka, Naoya Kuriyama, Akihiko Okamura, Yusuke Yamamoto, Asao Muranaka, Takahiro Ochiya\",\"doi\":\"10.1002/jev2.12461\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <p>Cardiac fibrosis is a common pathological feature of cardiovascular diseases that arises from the hyperactivation of fibroblasts and excessive extracellular matrix (ECM) deposition, leading to impaired cardiac function and potentially heart failure or arrhythmia. Extracellular vesicles (EVs) released by cardiomyocytes (CMs) regulate various physiological functions essential for myocardial homeostasis, which are disrupted in cardiac disease. Therefore, healthy CM-derived EVs represent a promising cell-free therapy for the treatment of cardiac fibrosis.</p>\\n </section>\\n \\n <section>\\n \\n <p>To this end, we optimized the culture conditions of human adult CMs to obtain a large yield of EVs without compromising cellular integrity by using a defined combination of small molecules. EVs were isolated by ultracentrifugation, and their characteristics were analysed. Finally, their effect on fibrosis was tested.</p>\\n </section>\\n \\n <section>\\n \\n <p>Treatment of TGFβ-activated human cardiac fibroblasts with EVs derived from CMs using our culture system resulted in a decrease in fibroblast activation markers and ECM accumulation. The rescued phenotype was associated with specific EV cargo, including multiple myocyte-specific and antifibrotic microRNAs, although their effect individually was not as effective as the EV treatment. Notably, pathway analysis showed that EV treatment reverted the transcription of activated fibroblasts and decreased several signalling pathways, including MAPK, mTOR, JAK/STAT, TGFβ, and PI3K/Akt, all of which are involved in fibrosis development. Intracardiac injection of CM-derived EVs in an animal model of cardiac fibrosis reduced fibrotic area and increased angiogenesis, which correlated with improved cardiac function.</p>\\n </section>\\n \\n <section>\\n \\n <p>These findings suggest that EVs derived from human adult CMs may offer a targeted and effective treatment for cardiac fibrosis, owing to their antifibrotic properties and the specificity of cargo.</p>\\n </section>\\n </div>\",\"PeriodicalId\":15811,\"journal\":{\"name\":\"Journal of Extracellular Vesicles\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":15.5000,\"publicationDate\":\"2024-06-28\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11211925/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Extracellular Vesicles\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/jev2.12461\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Extracellular Vesicles","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/jev2.12461","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
心脏纤维化是心血管疾病的常见病理特征,它源于成纤维细胞的过度活化和细胞外基质(ECM)的过度沉积,从而导致心脏功能受损,并可能引发心力衰竭或心律失常。心肌细胞(CM)释放的细胞外囊泡(EVs)调节着心肌稳态所必需的各种生理功能,而这些功能在心脏疾病中会受到破坏。因此,健康 CM 衍生的 EVs 是治疗心脏纤维化的一种前景广阔的无细胞疗法。为此,我们优化了人类成体 CM 的培养条件,通过使用特定的小分子组合,在不损害细胞完整性的情况下获得大量 EVs。我们通过超速离心法分离出了 EVs,并分析了它们的特征。最后,测试了它们对纤维化的影响。利用我们的培养系统,用从 CMs 提取的 EVs 处理 TGFβ 激活的人心脏成纤维细胞,结果发现成纤维细胞活化标记物和 ECM 积累减少。获救的表型与特定的 EV 货物有关,包括多种肌细胞特异性和抗纤维化的 microRNA,尽管它们的单独作用不如 EV 处理有效。值得注意的是,通路分析表明,EV处理可逆转活化成纤维细胞的转录,并减少几种信号通路,包括MAPK、mTOR、JAK/STAT、TGFβ和PI3K/Akt,所有这些通路都参与纤维化的发展。在心脏纤维化动物模型中,心内注射 CM 衍生的 EV 可减少纤维化面积并增加血管生成,这与心脏功能的改善相关。这些研究结果表明,从人类成体CM中提取的EVs由于其抗纤维化特性和货物的特异性,可为心脏纤维化提供有针对性的有效治疗。
Adult cardiomyocytes-derived EVs for the treatment of cardiac fibrosis
Cardiac fibrosis is a common pathological feature of cardiovascular diseases that arises from the hyperactivation of fibroblasts and excessive extracellular matrix (ECM) deposition, leading to impaired cardiac function and potentially heart failure or arrhythmia. Extracellular vesicles (EVs) released by cardiomyocytes (CMs) regulate various physiological functions essential for myocardial homeostasis, which are disrupted in cardiac disease. Therefore, healthy CM-derived EVs represent a promising cell-free therapy for the treatment of cardiac fibrosis.
To this end, we optimized the culture conditions of human adult CMs to obtain a large yield of EVs without compromising cellular integrity by using a defined combination of small molecules. EVs were isolated by ultracentrifugation, and their characteristics were analysed. Finally, their effect on fibrosis was tested.
Treatment of TGFβ-activated human cardiac fibroblasts with EVs derived from CMs using our culture system resulted in a decrease in fibroblast activation markers and ECM accumulation. The rescued phenotype was associated with specific EV cargo, including multiple myocyte-specific and antifibrotic microRNAs, although their effect individually was not as effective as the EV treatment. Notably, pathway analysis showed that EV treatment reverted the transcription of activated fibroblasts and decreased several signalling pathways, including MAPK, mTOR, JAK/STAT, TGFβ, and PI3K/Akt, all of which are involved in fibrosis development. Intracardiac injection of CM-derived EVs in an animal model of cardiac fibrosis reduced fibrotic area and increased angiogenesis, which correlated with improved cardiac function.
These findings suggest that EVs derived from human adult CMs may offer a targeted and effective treatment for cardiac fibrosis, owing to their antifibrotic properties and the specificity of cargo.
期刊介绍:
The Journal of Extracellular Vesicles is an open access research publication that focuses on extracellular vesicles, including microvesicles, exosomes, ectosomes, and apoptotic bodies. It serves as the official journal of the International Society for Extracellular Vesicles and aims to facilitate the exchange of data, ideas, and information pertaining to the chemistry, biology, and applications of extracellular vesicles. The journal covers various aspects such as the cellular and molecular mechanisms of extracellular vesicles biogenesis, technological advancements in their isolation, quantification, and characterization, the role and function of extracellular vesicles in biology, stem cell-derived extracellular vesicles and their biology, as well as the application of extracellular vesicles for pharmacological, immunological, or genetic therapies.
The Journal of Extracellular Vesicles is widely recognized and indexed by numerous services, including Biological Abstracts, BIOSIS Previews, Chemical Abstracts Service (CAS), Current Contents/Life Sciences, Directory of Open Access Journals (DOAJ), Journal Citation Reports/Science Edition, Google Scholar, ProQuest Natural Science Collection, ProQuest SciTech Collection, SciTech Premium Collection, PubMed Central/PubMed, Science Citation Index Expanded, ScienceOpen, and Scopus.