Anti-inflammatory, Anti-fibrotic and Pro-cardiomyogenic Effects of Genetically Engineered Extracellular Vesicles Enriched in miR-1 and miR-199a on Human Cardiac Fibroblasts
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Published:2023-09-13
Issue:8
Volume:19
Page:2756-2773
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ISSN:2629-3269
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Container-title:Stem Cell Reviews and Reports
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language:en
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Short-container-title:Stem Cell Rev and Rep
Author:
Kmiotek-Wasylewska Katarzyna, Bobis-Wozowicz Sylwia, Karnas Elżbieta, Orpel Monika, Woźnicka Olga, Madeja Zbigniew, Dawn Buddhadeb, Zuba-Surma Ewa K.ORCID
Abstract
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.
Graphical Abstract
Funder
Narodowe Centrum Nauki
Publisher
Springer Science and Business Media LLC
Reference56 articles.
1. Roth, G. A., Mensah, G. A., Johnson, C. O., Addolorato, G., Ammirati, E., Baddour, L. M., Barengo, N. C., Beaton, A. Z., Benjamin, E. J., Benziger, C. P., et al. (2020). Global burden of cardiovascular diseases and risk factors, 1990–2019: Update from the GBD 2019 study. Journal of the American College of Cardiology, 76(25), 2982–3021. https://doi.org/10.1016/j.jacc.2020.11.010 2. Hashimoto, H., Olson, E. N., & Bassel-Duby, R. (2018). Therapeutic approaches for cardiac regeneration and repair. Nature Reviews Cardiology, 15(10), 585–600. https://doi.org/10.1038/s41569-018-0036-6 3. Li, X., Tamama, K., Xie, X., & Guan, J. (2016). Improving cell engraftment in cardiac stem cell therapy. Stem Cells International, 2016, 7168797. https://doi.org/10.1155/2016/7168797 4. Ong, S. B., Hernandez-Resendiz, S., Crespo-Avilan, G. E., Mukhametshina, R. T., Kwek, X. Y., Cabrera-Fuentes, H. A., & Hausenloy, D. J. (2018). Inflammation following acute myocardial infarction: Multiple players, dynamic roles, and novel therapeutic opportunities. Pharmacology & Therapeutics, 186, 73–87. https://doi.org/10.1016/j.pharmthera.2018.01.001 5. Travers, J. G., Kamal, F. A., Robbins, J., Yutzey, K. E., & Blaxall, B. C. (2016). Cardiac fibrosis: The fibroblast awakens. Circulation Research, 118(6), 1021–1040. https://doi.org/10.1161/CIRCRESAHA.115.306565
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