Abstract
Cardiomyocyte progenitor cells play essential roles in early heart development, which requires highly controlled cellular organization. microRNAs (miRs) are involved in various cell behaviors by post-transcriptional regulation of target genes. However, the roles of miRNAs in human cardiomyocyte progenitor cells (hCMPCs) remain to be elucidated. Our previous study showed that miR-134 was significantly downregulated in heart tissue suffering from congenital heart disease, underlying the potential role of miR-134 in cardiogenesis. In the present work, we showed that the upregulation of miR-134 reduced the proliferation of hCMPCs, as determined by EdU assay and Ki-67 immunostaining, while the inhibition of miR-134 exhibited an opposite effect. Both up- and downregulation of miR-134 expression altered the transcriptional level of cell-cycle genes. We identified Meis2 as the target of miR-134 in the regulation of hCMPC proliferation through bioinformatic prediction, luciferase reporter assay and western blot. The over-expression of Meis2 mitigated the effect of miR-134 on hCMPC proliferation. Moreover, miR-134 did not change the degree of hCMPC differentiation into cardiomyocytes in our model, suggesting that miR-134 is not required in this process. These findings reveal an essential role for miR-134 in cardiomyocyte progenitor cell biology and provide new insights into the physiology and pathology of cardiogenesis.
Highlights
Cardiomyocyte progenitor cells arise in the mesodermal layer at the embryonic stage and contribute to the final shape of the heart with its morphologically distinct compartments [1]
We found that miR-134 could regulate human cardiomyocyte progenitor cells (hCMPCs) proliferation and target the transcription factor myeloid ecotropic insertion site 2 (Meis2), which is involved in various developmental programs [14]
We found that modulation of miR-134 expression did not change the degree of hCMPC differentiation into cardiomyocytes in our model, suggesting that miR-134 is not required in this process
Summary
Cardiomyocyte progenitor cells arise in the mesodermal layer at the embryonic stage and contribute to the final shape of the heart with its morphologically distinct compartments [1]. In addition in to the embryonic heart, resident cardiac progenitor cells have been identified in adults [3]. These cells, which have shown the potential to form cardiomyocytes, smooth muscle cells, and endothelial cells in vitro and in vivo, could potentially be used as a source for cardiac repair [4]. Identification of miRs in different heart diseases has led to the exploration of regulatory roles for these small RNAs during cardiomyocyte differentiation, cell cycle, and cardiac hypertrophy [7]. MiR-134 was significantly downregulated in TOF patients, suggesting the potential role of miR-134 in the heart development and proliferation/differentiation of hCMPCs. Here, we sought to explore the effects of miR-134 on hCMPCs and reveal its mechanism of function. Meis overexpression rescues the phenotype of miR-134 in hCMPCs
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