The optimization of cell therapy by combinational application with apicidin-treated mesenchymal stem cells after myocardial infarction

Abstract

Although mesenchymal stem cells (MSC) have been shown to be safe in preclinical studies of cardiovascular disease, multiple meta-analyses have debated whether functional improvement is significant or not. The cardiac differentiation from MSC is achievable using cardiogenic factors, however, the high cost and long culture period may limit the applications. Here, we developed a novel method to optimize the therapeutic outcome for myocardial infarction (MI). Treatment of MSC with apicidin, a histone deacetylase inhibitor, dramatically increased the expressions of cardiac markers such as GATA4, Nkx2.5, and cardiac troponin I (cTnI). In AC/MSC, stemness-related genes and yes-associated protein (YAP), a potent oncogene that drives cell proliferation, were significantly suppressed. Furthermore apicidin treatment or YAP knockdown downregulated miR-130a expression followed by induction of cardiac markers in MSC. In the comparison study, we found that both cardiac gene induction and angiogenesis were most prominent in the mixture of non-treated MSC and AC/MSC (Mix). Using mouse MI model, we show that application of Mix was strongly associated with cardiac differentiation of injected MSC and improved cardiac performance. Our results suggest that suppression of YAP/miR-130a shifts MSC cell fate toward cardiac lineage and identify apicidin as a potential pharmacological target for therapeutic development.

Troponin through the looking-glass: emerging roles beyond regulation of striated muscle contraction

“…These findings suggest the possibility of a signal-dependent role for nuclear cTnI in cardiac hypertrophy. In another report, cTnI was identified in the nuclei, but not the cytoplasm of mesenchymal stem cells (MSCs) treated with the histone deacetylase inhibitor, apicidin [ 138 ]. Apicidin treatment was associated with commitment of MSCs to the cardiac lineage—which, when combined with untreated MSCs, lead to improved cardiac function in an animal model of myocardial infarction.…”

“…Apicidin treatment was associated with commitment of MSCs to the cardiac lineage—which, when combined with untreated MSCs, lead to improved cardiac function in an animal model of myocardial infarction. In this study, a mechanism involving YAP/miR-130a was invoked [ 138 ]. Based on these findings and a previous report [ 35 ], it is enticing to speculate that nuclear cTnI, along with other troponin subunits, might be involved in the processes related to cardiomyocyte differentiation.…”

Antiinflammatory activity of ANGPTL4 facilitates macrophage polarization to induce cardiac repair

“…Mesenchymal stem cell-mediated (MSC-mediated) regeneration therapy has been widely applied for cardiovascular disease (1)(2)(3)(4). MSCs effect tissue repair largely via their paracrine factors and by activating endogenous progenitor cells, not only by cell replacement (1,5,6).…”

Adjuvant role of macrophages in stem cell-induced cardiac repair in rats

“…Despite the safety and feasibility of BMMSCs, concerns over their use remain due to equivocal clinical outcomes 4 . Various modifications have been proposed to improve the therapeutic efficacy of BMMSCs in cardiovascular disorders, such as priming with growth factors, cardiogenic cocktails, or apicidin or hypoxia-enhanced functional restoration via angiogenesis and cardiac differentiation 5 – 7 .…”