MicroRNAs (miRNAs) are a class of noncoding RNAs about 22 nucleotides long that can act as negative regulators of gene expression by binding to the 3′ UTR of mRNAs [19]. Previous studies have confirmed that miRNAs can play a significant role in cell development, differentiation, proliferation, and apoptosis [20]. Studies have also demonstrated that miRNAs can regulate differentiation of BMSCs [21, 22]. However, whether miRNAs could regulate cardiomyocyte differentiation of BMSCs is still little known.

Zhao et al.’s [23] study reveals that miR-1a could promote the differentiation of BMSCs into myocardial cells. Their results show that BMSCs could differentiate into myocardial cells in special conditioned medium, but will be efficient when overexpressing miR-1a. As an in-depth study, they demonstrate that Delta-like 1 (Dll-1) is the key inhibitor of myocardium gene expression during myocardium differentiation and that miR-1a can reduce the expression of Dll-1 by targeting the 3′ UTR, leading to the dramatic upregulation of myocardium gene protein.

Cai et al. [24] show that BMSCs are transformed into cardiomyocytes by coculture with cardiomyocytes, and cardiac-specific markers such as atrial natriuretic peptide (ANP), cardiac troponin T (cTnT), and α-myosin heavy chain (α-MHC) are detected. miRNA assay indicates that the level of miR-124 is significantly downregulated during cardiomyocte differentiation of BMSCs. The authors then performed functional experiments on the acquisition or loss of miR-124 and find that overexpression of miR-124 would inhibit cardiomyocyte differentiation of BMSCs. By further study into the molecular mechanism of this progress, the authors demonstrate that miR-124 exerts a negative effect on myogenic differentiation of BMSCs via targeting signal transducers and activators of transcription 3 (STAT3) [24].

Shen et al. [25] find the expression of miR1-2 is significantly increased after 5-aza treatment. In order to clear the role of miR1-2 in modulating cardiomyocyte differentiation, miR1-2 mimics are transferred into BMSCs, and these cells are induced to differentiate into cardiomyocytes by the expression of cardiac-specific genes GATA binding protein 4 (GATA4), cardiac troponin I (cTnI), and Homeobox protein 2.5 (Nkx2.5). Further study shows that miR1-2 could activate the Wnt/β-catenin signaling pathway, whereas BMSCs pretreated with Wnt/β-catenin signaling inhibitor LGK-974 can weaken the differentiation of BMSCs into cardiomyocytes. To sum up, miR1-2 could regulate the differentiation of BMSCs into cardiomyocytes via the Wnt/β-catenin signaling pathway [25].

miRNAs could regulate gene expression and the cardiomyocyte development and differentiation of stem cells [26], including BMSCs. For instance, miR-23b inhibits the osteogenic differentiation of BMSCs via targeting Runx2 during treatment with TNF-α [27]. The miR-1/133 family has a high level in the heart, but they have opposing effects: miR-1 promotes and miR-133 blocks differentiation into cardiac cells. A previous study has shown that Jagged 1 protein could activate Notch signal and promote the differentiation of BMSCs into cardiomyocytes in vitro and in vivo [28], and miR-1 could promote myocardial differentiation in stem cells via targeting Dll-1, a Notch ligand expressed in ES cells [29]. The Wnt signaling pathway has an essential role in cardiomyocyte development and β-catenin could promote the occurrence of the heart in Drosophila [30]. The Wnt signaling pathway also regulates the proliferation and differentiation of BMSCs [31]. miR-29c-3p is significantly upregulated and could regulate the osteoblast differentiation of rat BMSCs by targeting Dishevelled 2, a key mediator of the Wnt/β-catenin signaling pathway, in a hyperlipidemia environment [32]. Therefore, the increasing in miR-124 level is considered to be an important trigger of the transition from proliferation to neural differentiation [33]. STAT3 has a significant role in self-renewal, differentiation, and paracrine activation of BMSCs [7, 34]. Activation of STAT3 has been reported that could enhance the differentiation of transplanted BMSCs and produce better function of infarcted myocardium. miR-124 regulates the activation of STAT3 and in turn affects myogenic differentiation of BMSCs.

The miRNAs mimics group have a lower apopotic rate than the 5-aza group, indicating miRNAs are less cytotoxic. BMSCs treated with miRNAs express cardiac-specific genes but these cells are still short of the morphology of cardiomyocytes, indicating that further investigation needs to be done. Long noncoding RNAs have been shown to play important roles in multiple physiological processes. Nowadays, lncRNA H19 could mediate osteogenesis differentiation of BMSCs by sponging miR-138 [35]. This might be a new strategy to induce cardiomyocyte differentiation of BMSCs through miRNAs.