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富含 miR-1 和 miR-199a 的基因工程细胞外囊泡对人心脏成纤维细胞的抗炎、抗纤维化和促心肌生成作用。

Anti-inflammatory, Anti-fibrotic and Pro-cardiomyogenic Effects of Genetically Engineered Extracellular Vesicles Enriched in miR-1 and miR-199a on Human Cardiac Fibroblasts.

机构信息

Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Krakow, Poland.

Department of Cell Biology and Imaging, Institute of Zoology and Biomedical Research, Jagiellonian University, Gronostajowa 7, 30-387, Kraków, Poland.

出版信息

Stem Cell Rev Rep. 2023 Nov;19(8):2756-2773. doi: 10.1007/s12015-023-10621-2. Epub 2023 Sep 13.

DOI:10.1007/s12015-023-10621-2
PMID:37700183
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10661813/
Abstract

RATIONALE

Emerging evidence indicates that stem cell (SC)- derived extracellular vesicles (EVs) carrying bioactive miRNAs are able to repair damaged or infarcted myocardium and ameliorate adverse remodeling. Fibroblasts represent a major cell population responsible for scar formation in the damaged heart. However, the effects of EVs on cardiac fibroblast (CFs) biology and function has not been investigated.

OBJECTIVE

To analyze the biological impact of stem cell-derived EVs (SC-EVs) enriched in miR-1 and miR-199a on CFs and to elucidate the underlying molecular mechanisms.

METHODS AND RESULTS

Genetically engineered human induced pluripotent stem cells (hiPS) and umbilical cord-derived mesenchymal stem cells (UC-MSCs) expressing miR-1 or miR-199a were used to produce miR-EVs. Cells and EVs were thoughtfully analyzed for miRNA expression using RT-qPCR method. Both hiPS-miRs-EVs and UC-MSC-miRs-EVs effectively transferred miRNAs to recipient CFs, however, hiPS-miRs-EVs triggered cardiomyogenic gene expression in CFs more efficiently than UC-MSC-miRs-EVs. Importantly, hiPS-miR-1-EVs exhibited cytoprotective effects on CFs by reducing apoptosis, decreasing levels of pro-inflammatory cytokines (CCL2, IL-1β, IL-8) and downregulating the expression of a pro-fibrotic gene - α-smooth muscle actin (α-SMA). Notably, we identified a novel role of miR-199a-3p delivered by hiPS-EVs to CFs, in triggering the expression of cardiomyogenic genes (NKX2.5, TNTC, MEF2C) and ion channels involved in cardiomyocyte contractility (HCN2, SCN5A, KCNJ2, KCND3). By targeting SERPINE2, miR-199a-3p may reduce pro-fibrotic properties of CFs, whereas miR-199a-5p targeted BCAM and TSPAN6, which may be implicated in downregulation of inflammation.

CONCLUSIONS

hiPS-EVs carrying miR-1 and miR-199a attenuate apoptosis and pro-fibrotic and pro-inflammatory activities of CFs, and increase cardiomyogenic gene expression. These finding serve as rationale for targeting fibroblasts with novel EV-based miRNA therapies to improve heart repair after myocardial injury.

摘要

背景

新出现的证据表明，携带生物活性 miRNA 的干细胞（SC）衍生细胞外囊泡（EVs）能够修复受损或梗死的心肌，并改善不良重构。成纤维细胞是负责损伤心脏瘢痕形成的主要细胞群体。然而，EVs 对心脏成纤维细胞（CFs）生物学和功能的影响尚未得到研究。

目的

分析富含 miR-1 和 miR-199a 的干细胞衍生 EVs（SC-EVs）对 CFs 的生物学影响，并阐明潜在的分子机制。

方法和结果

使用基因工程人诱导多能干细胞（hiPS）和脐带间充质干细胞（UC-MSCs）表达 miR-1 或 miR-199a 来产生 miR-EVs。使用 RT-qPCR 方法仔细分析细胞和 EVs 的 miRNA 表达。hiPS-miRs-EVs 和 UC-MSC-miRs-EVs 均可有效地将 miRNA 转移至受体 CFs，但 hiPS-miRs-EVs 比 UC-MSC-miRs-EVs 更有效地触发 CFs 的心肌生成基因表达。重要的是，hiPS-miR-1-EVs 通过减少细胞凋亡、降低促炎细胞因子（CCL2、IL-1β、IL-8）水平和下调促纤维化基因-α平滑肌肌动蛋白（α-SMA）的表达，对 CFs 发挥细胞保护作用。值得注意的是，我们发现 hiPS-EVs 向 CFs 递送的 miR-199a-3p 具有触发心肌生成基因（NKX2.5、TNTC、MEF2C）和参与心肌收缩的离子通道（HCN2、SCN5A、KCNJ2、KCND3）表达的新作用。通过靶向 SERPINE2，miR-199a-3p 可能降低 CFs 的促纤维化特性，而 miR-199a-5p 靶向 BCAM 和 TSPAN6，这可能与炎症下调有关。

结论

携带 miR-1 和 miR-199a 的 hiPS-EVs 可减轻 CFs 的细胞凋亡和促纤维化及促炎活性，并增加心肌生成基因表达。这些发现为利用新型 EV 基于 miRNA 的治疗方法靶向成纤维细胞以改善心肌损伤后的心脏修复提供了依据。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac94/10661813/4ca6d1311e94/12015_2023_10621_Fig7_HTML.jpg
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