Abstract
BackgroundTransplanted mesenchymal stem cells (MSC) can differentiate into cardiac cells that have the potential to contribute to heart repair following ischemic injury. Overexpression of GATA-4 can significantly increase differentiation of MSC into cardiomyocytes (CM). However, the specific impact of GATA-4 overexpression on the electrophysiological properties of MSC-derived CM has not been well documented. MethodsAdult rat bone marrow MSC were retrovirally transduced with GATA-4 (MSCGATA-4) and GFP (MSCNull) and subsequently co-cultured with neonatal rat ventricular cardiomyocytes (CM). Electrophysiological properties and mRNA levels of ion channels were assessed in MSC using patch-clamp technology and real-time PCR. ResultsMSCGATA-4 exhibited higher levels of the TTX-sensitive Na+ current (INa.TTX), L-type calcium current (ICa.L), transient outward K+ current (Ito), delayed rectifier K+ current (IKDR) and inwardly rectifying K+ current (IK1) channel activities reflective of electrophysiological characteristics of CM. Real-time PCR analyses showed that MSCGATA-4 exhibited upregulated mRNA levels of Kv1.2, Kv2.1, SCN2a1, CCHL2a, KV1.4 and Kir1.1 channels versus MSCNull. Interestingly, MSCGATA-4 treated with IGF-1 neutralizing antibodies resulted in a significant decrease in Kir1.1, Kv2.1, KV1.4, CCHL2a and SCN2a1 channel mRNA expression. Similarly, MSCGATA-4 treated with VEGF neutralizing antibodies also resulted in an attenuated expression of Kv2.1, Kv1.2, Kv1.4, Kir1.1, CCHL2a and SCN2a1 channel mRNAs. ConclusionsGATA-4 overexpression increases Ito, IKDR, IK1, INa.TTX and ICa.L currents in MSC. Cytokine (VGEF and IGF-1) release from GATA-4 overexpressing MSC can partially account for the upregulated ion channel mRNA expression. General significanceOur results highlight the ability of GATA4 to boost the cardiac electrophysiological potential of MSC.
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