Oncotarget

Research Papers:

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

Dong Im Cho, Wan Seok Kang, Moon Hwa Hong, Hye Jin Kang, Mi Ra Kim, Min Chul Kim, Yong Sook Kim and Youngkeun Ahn _

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Oncotarget. 2017; 8:44281-44294. https://doi.org/10.18632/oncotarget.17471

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Abstract

Dong Im Cho1, Wan Seok Kang1, Moon Hwa Hong1, Hye Jin Kang1, Mi Ra Kim1, Min Chul Kim2, Yong Sook Kim1,3 and Youngkeun Ahn1,2

1Cell Regeneration Research Center, Chonnam National University Hospital, Gwangju, South Korea

2Department of Cardiology, Chonnam National University Hospital, Gwangju, South Korea

3Biomedical Research Institute, Chonnam National University Hospital, Gwangju, South Korea

Correspondence to:

Youngkeun Ahn, email: [email protected]

Yong Sook Kim, email: [email protected]

Keywords: mesenchymal stem cell, myocardial infarction, apicidin, differentiation, cotransplantation

Received: March 13, 2017    Accepted: April 16, 2017    Published: April 27, 2017

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.


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