Christopher Story

Background: A Myocardial Infarction (MI) is a life-threatening cardiac event that afflicts over 800,000 individuals every year in the United States alone resulting in either fatality or a significant reduction in heart function.¹ MI’s occur when one or more coronary arteries become occluded leading to a lack of nutrients and oxygen to downstream cardiac tissue inducing cell death and initiating an inflammatory response.^1,2 Macrophages have been observed to play a significant role in this inflammatory response in a time-dependent manner.³ It has been characterized that pro-inflammatory M1 macrophages are present in tissue in the first 72 hours following MI insult which are then replaced by anti-inflammatory M2 macrophages that help in the resolution of inflammation, which when resolved, leaves a nonfunctional fibrotic patch.^2,3 Due to the drastic improvement of MI survivability from 50% to upwards of 90% there are more patients than ever before living with nonfunctional fibrotic patches within their heart reducing their life expectancy and quality of life.¹ While there are no current treatment modalities to address this unmet concern, Mesenchymal Stem Cells (MSCs) and the exosomes they secrete have been observed to provide immunomodulatory effects that could be therapeutically leveraged to alleviate some of the functional deficits MI patients are left with.^4-7

Objective: In this narrative review, we explored the use and mechanisms of MSC exosomes within a MI model to reduce functional deficits through inducing M1 to M2 macrophage polarization.

Search Methods: Online PubMed database search was conducted for articles from 2017 to 2023 using the following keywords: “myocardial infarction”, “mesenchymal stem cells”, “macrophage polarization”, “exosomes”.

Results: Previous studies have shown that MSCs alone were able to reduce myocardial fibrosis, reduce disruption of cardiac architecture, and reduce the presence of the pro-inflammatory cytokines IL-6 and TNF-a.⁴ This was in shown to correspond with the polarizing shift of macrophages from M1 to M2 following MSC cardiac infusion.⁴ Subsequent studies investigated the use of exosomes secreted by MSCs to provide similar effects. Results indicated that not only was exosome infusion able to significantly improve the left ventricular injection fraction and left ventricular fractional shortening when compared to no treatment, but exosomes also significantly outperformed whole MSC infusions.⁵ Infarct size and cardiomyocyte apoptosis rate were also significantly improved following MSC exosome infusion.⁵ Additional studies validated that the results produced by exosomes were connected to an M1 to M2 macrophage polarizing shift following treatment.⁶ Lastly, a mechanistic study implicated miRNA-182 as the causative cargo delivered by exosomes that inhibits expression of Toll-Like Receptor 4 within macrophages present at the site of infection inducing their shift from M1 to M2 and thus a reduction in local inflammation.⁷

Conclusions: These data suggest MSC-derived exosomes posses immunomodulatory function-saving cargo displayed within the MI model through M1 to M2 macrophage polarization induced by TLR4 downregulation mediated by the delivery of miRNA-182 thus leading to improved MI outcomes. While MI survival has increased significantly, the need for treatments of the lasting functional deficits implicates the potential importance of MSC-derived exosomes.

Works Cited:

1. Tsao CW, Aday AW, Almarzooq ZI, et al. Heart Disease and Stroke Statistics-2022 Update: A Report From the American Heart Association [published correction appears in Circulation. 2022 Sep 6;146(10):e141]. Circulation. 2022;145(8):e153-e639. doi:10.1161/CIR.0000000000001052
2. Kologrivova I, Shtatolkina M, Suslova T, Ryabov V. Cells of the Immune System in Cardiac Remodeling: Main Players in Resolution of Inflammation and Repair After Myocardial Infarction. Front Immunol. 2021 Apr 2;12:664457. doi:10.3389/fimmu.2021.664457
3. Mouton AJ, DeLeon-Pennell KY, Rivera Gonzalez OJ, Flynn ER, Freeman TC, Saucerman JJ, Garrett MR, Ma Y, Harmancey R, Lindsey ML. Mapping macrophage polarization over the myocardial infarction time continuum. Basic Res Cardiol. 2018 Jun 4;113(4):26. doi: 10.1007/s00395-018-0686-x.
4. Jin L, Deng Z, Zhang J, et al. Mesenchymal stem cells promote type 2 macrophage polarization to ameliorate the myocardial injury caused by diabetic cardiomyopathy. J Transl Med. 2019;17(1):251. Published 2019 Aug 5. doi:10.1186/s12967-019-1999-8
5. Xu H, Wang Z, Liu L, Zhang B, Li B. Exosomes derived from adipose tissue, bone marrow, and umbilical cord blood for cardioprotection after myocardial infarction. J Cell Biochem. 2020;121(3):2089-2102. doi:10.1002/jcb.27399
6. Xu R, Zhang F, Chai R, et al. Exosomes derived from pro-inflammatory bone marrow-derived mesenchymal stem cells reduce inflammation and myocardial injury via mediating macrophage polarization. J Cell Mol Med. 2019;23(11):7617-7631. doi:10.1111/jcmm.14635
7. Zhao J, Li X, Hu J, et al. Mesenchymal stromal cell-derived exosomes attenuate myocardial ischaemia-reperfusion injury through miR-182-regulated macrophage polarization. Cardiovasc Res. 2019;115(7):1205-1216. doi:10.1093/cvr/cvz040