MicroRNA-133 overexpression promotes the therapeutic efficacy of mesenchymal stem cells on acute myocardial infarction

Abstract

Background: Our study aim was to evaluate the therapeutic efficacy and mechanisms of miR-133-overexpressing mesenchymal stem cells (MSCs) on acute myocardial infarction. Methods: Rat MSCs were isolated and purified by whole bone marrow adherent culturing. After transfection with the agomir or antagomir of miR-133, MSCs were collected for assay of cell vitality, apoptosis, and cell cycle progression. At the same time, exosomes were isolated from the supernatant to analyze the paracrine miR-133. For in-vivo studies, constitutive activation of miR-133 in MSCs was achieved by lentivirus-mediated miR-133 overexpression. A rat myocardial infarction model was created by ligating the left anterior descending coronary artery, while control MSCs (vector-MSCs) or miR-133-overexpressed MSCs (miR-133-MSCs) were injected into the zone around the myocardial infarction. Subsequently, myocardial function was evaluated by echocardiography on days 7 and 28 post infarction. Finally the infarcted hearts were collected on days 7 and 28 for myocardial infarct size measurement and detection of snail 1 expression. Results: Hypoxia-induced apoptosis of MSCs obviously reduced, along with enhanced expression of total poly ADP-ribose polymerase protein, after miR-133 agomir transfection, while the apoptosis rate increased in MSCs transfected with miR-133 antagomir. However, no change in cell viability and cell-cycle distribution was observed in control, miR-133-overexpressed, and miR-133-interfered MSCs. Importantly, rats transplanted with miR-133-MSCs displayed more improved cardiac function after acute myocardial infarction, compared with those that received vector-MSC injection. Further studies indicated that cardiac expression of snail 1 was significantly repressed by adjacent miR-133-overexpressing MSCs, and both the inflammatory level and the infarct size decreased in miR-133-MSC-injected rat hearts.

Downregulation of miRNA‑663b protects against hypoxia‑induced injury in cardiomyocytes by targeting BCL2L1

“…Cardiomyocyte apoptosis is one of the primary types of cardiac cell death during MI (23). Protecting cardiomyocytes against hypoxia-induced damage may therefore be a promising therapeutic target for the treatment of MI (24)(25)(26).…”

MiR-133a-3p transferred by circulating microvesicles derived from myocardial ischemic preconditioning protects cardiomyocytes against hypoxia/reoxygenation injury

“…MiR-133 has been proved to improve cardiac function in a rat model of myocardial infarction. Mesenchymal stem cells with overexpressed miR-133 can reduce the infarct size and decrease the inflammatory level [22]. MiR-378 known as angio-miRNA is a key regulator of angiogenesis, which could regulate the angiogenic capacity of CD34 + progenitor cells in vivo, suggesting that this unique miRNA expression pattern represented a novel endogenous repair mechanism activated in acute myocardial infarction [26].…”

“…4c). Meanwhile, miR-133a-3p, a highly expressed miRNA in heart, was widely involved in the regulation of cell differentiation [19], angiogenesis [20], cardiac hypertrophy and fibrosis [21], cell apoptosis [14] and myocardial repair [22], et al These data pointed to the miR-133a-3p as a strong candidate for the key regulatory cargo contained in IPC-MVs.…”

Inhibition of cardiac allograft rejection in mice using interleukin‐35‐modified mesenchymal stem cells

“…For example, miR‐122‐transfected MSCs effectively packaged miR‐122 into secreted exosomes, and these exosomes could significantly increase the curative effects of sorafenib on hepatocarcinoma . In another study, miR‐133‐transfected MSCs effectively decreased the inflammatory level and infarct size in rat hearts, and the miR‐133 levels in exosomes isolated from miR‐133‐transfected MSC culture supernatants were elevated by 200‐fold compared with that in the negative control group . Therefore, whether the exosomes secreted by IL‐35‐MSCs can also transfer IL‐35, miRNAs or other substances to target cells to exert their effects after IL‐35 gene modification and whether this is a mechanism underlying the stronger immunomodulatory effect, and thus better allograft rejection ability, of IL‐35‐MSCs compared to that of MSCs remain unknown, and these questions are the focus of our next research.…”