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Knockdown of deleterious miRNA in progenitor cell-derived small extracellular vesicles enhances tissue repair in myocardial infarction.

ABSTRACT: Small extracellular vesicles (sEVs) play a critical role in cardiac cell therapy by delivering molecular cargo and mediating cellular signaling. Among sEV cargo molecule types, microRNA (miRNA) is particularly potent and highly heterogeneous. However, not all miRNAs in sEV are beneficial. Two previous studies using computational modeling identified miR-192-5p and miR-432-5p as potentially deleterious in cardiac function and repair. Here, we show that knocking down miR-192-5p and miR-432-5p in cardiac c-kit⁺ cell (CPC)-derived sEVs enhances the therapeutic capabilities of sEVs in vitro and in a rat in vivo model of cardiac ischemia reperfusion. miR-192-5p- and miR-432-5p-depleted CPC-sEVs enhance cardiac function by reducing fibrosis and necrotic inflammatory responses. miR-192-5p-depleted CPC-sEVs also enhance mesenchymal stromal cell-like cell mobilization. Knocking down deleterious miRNAs from sEV could be a promising therapeutic strategy for treatment of chronic myocardial infarction.

SUBMITTER: Park HJ

PROVIDER: S-EPMC9984177 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Knockdown of deleterious miRNA in progenitor cell-derived small extracellular vesicles enhances tissue repair in myocardial infarction.

Park Hyun-Ji HJ Hoffman Jessica R JR Brown Milton E ME Bheri Sruti S Brazhkina Olga O Son Young Hoon YH Davis Michael E ME

Science advances 20230303 9

Small extracellular vesicles (sEVs) play a critical role in cardiac cell therapy by delivering molecular cargo and mediating cellular signaling. Among sEV cargo molecule types, microRNA (miRNA) is particularly potent and highly heterogeneous. However, not all miRNAs in sEV are beneficial. Two previous studies using computational modeling identified miR-192-5p and miR-432-5p as potentially deleterious in cardiac function and repair. Here, we show that knocking down miR-192-5p and miR-432-5p in ca ...[more]

PMID: 36867699

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Project description:Myocardial infarction (MI), a main cause of heart failure, leads to irreversible cardiomyocytes loss and cardiac function impairment. Current clinical treatments for MI are largely ineffective as they mostly aim to alleviate symptoms rather than repairing the injured myocardium. Thus, development of more effective therapies is compelling. This study aims to investigate whether the extracellular vesicles (EVs) carrying specific anti-apoptotic miRNA can be efficiently internalized into myocardium to achieve desired therapeutic outcomes. Methods: EVs were isolated from HEK293T cells overexpressing miRNA-21 (miR21-EVs) and identified. The RNase resistant rate of miR21-EVs was calculated by real-time PCR and compared with liposomes and polyethylenimine (PEI). Confocal laser scanning microscopy was used for visualizing the cellular internalization of miR21-EVs in primary cultured mouse neonatal cardiomyocytes (CMs), H9c2 rat cardiomyoblasts, and human umbilical vein endothelial cells (HUVECs). The effect of miR21-EVs on the expression of PDCD4, a pro-apoptotic protein that plays an important role in regulating myocardial apoptosis, was also evaluated in these three cell types by real-time PCR and Western blot analysis. In vivo, miR21-EVs was directly injected into the infarct zone following ligation of the left anterior descending of coronary artery in mice. The miR21-EVs distribution and blood vessel (capillary and arteriole) density were evaluated by immunofluorescence staining. Fluorescence in situ hybridization of miRNA-21 was also carried out to confirm the miR21-EVs distribution in vitro and in vivo. The protein level of PDCD4 in myocardium was assessed by immunohistochemical staining. The anti-apoptotic effect of miR21-EVs in cardiomyocytes and endothelial cells were measured using TUNEL staining. Four weeks after injection, the cardiac histological and functional recovery was evaluated by histochemistry staining and echocardiography, respectively. Results: In contrast to liposomes and PEI, EVs significantly inhibited miRNA-21 degradation. MiR21-EVs efficiently delivered miRNA-21 into cardiomyocytes and endothelial cells within 4 hours. Exogenous miRNA-21 in turn significantly reduced PDCD4 expression and attenuated cell apoptosis in vitro. Consistently and importantly, in a preclinical MI animal model, miRNA-21-loaded EVs effectively sent miRNA-21 into cardiomyocytes and endothelial cells, drastically inhibited cell apoptosis and led to significant cardiac function improvement. Conclusion: Our results suggest the cell-derived, genetically engineered EVs may be used therapeutically for the delivery of miRNAs for the rescue of MI and may benefit patients in the future.

Dataset Information

Knockdown of deleterious miRNA in progenitor cell-derived small extracellular vesicles enhances tissue repair in myocardial infarction.

Publications

Knockdown of deleterious miRNA in progenitor cell-derived small extracellular vesicles enhances tissue repair in myocardial infarction.

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