Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, USA.
Am J Physiol Heart Circ Physiol. 2011 Nov;301(5):H2038-49. doi: 10.1152/ajpheart.00271.2011. Epub 2011 Aug 19.
microRNAs (miRs) have emerged as critical modulators of various physiological processes including stem cell differentiation. Indeed, miR-1 has been reported to play an integral role in the regulation of cardiac muscle progenitor cell differentiation. However, whether overexpression of miR-1 in embryonic stem (ES) cells (miR-1-ES cells) will enhance cardiac myocyte differentiation following transplantation into the infarcted myocardium is unknown. In the present study, myocardial infarction (MI) was produced in C57BL/6 mice by left anterior descending artery ligation. miR-1-ES cells, ES cells, or culture medium (control) was transplanted into the border zone of the infarcted heart, and 2 wk post-MI, cardiac myocyte differentiation, adverse ventricular remodeling, and cardiac function were assessed. We provide evidence demonstrating enhanced cardiac myocyte commitment of transplanted miR-1-ES cells in the mouse infarcted heart as compared with ES cells. Assessment of apoptosis revealed that overexpression of miR-1 in transplanted ES cells protected host myocardium from MI-induced apoptosis through activation of p-AKT and inhibition of caspase-3, phosphatase and tensin homolog, and superoxide production. A significant reduction in interstitial and vascular fibrosis was quantified in miR-1-ES cell and ES cell transplanted groups compared with control MI. However, no statistical significance between miR-1-ES cell and ES cell groups was observed. Finally, mice receiving miR-1-ES cell transplantation post-MI had significantly improved heart function compared with respective controls (P < 0.05). Our data suggest miR-1 drives cardiac myocyte differentiation from transplanted ES cells and inhibits apoptosis post-MI, ultimately giving rise to enhanced cardiac repair, regeneration, and function.
微小 RNA（miRs）已成为各种生理过程的关键调节剂，包括干细胞分化。事实上，miR-1 已被报道在心肌前体细胞分化的调节中发挥重要作用。然而，在胚胎干细胞（ES 细胞）中转录物的过表达（miR-1-ES 细胞）是否会增强移植到梗死心肌后的心肌细胞分化尚不清楚。在本研究中，通过左前降支结扎在 C57BL/6 小鼠中产生心肌梗死（MI）。将 miR-1-ES 细胞、ES 细胞或培养基（对照）移植到梗死心脏的边缘区，MI 后 2 周，评估心肌细胞分化、心室重构和心脏功能。我们提供的证据表明，与 ES 细胞相比，miR-1-ES 细胞在小鼠梗死心脏中的心肌细胞分化增强。凋亡评估表明，miR-1 在移植的 ES 细胞中的过表达通过激活 p-AKT 和抑制 caspase-3、磷酸酶和张力蛋白同源物和超氧化物的产生来保护宿主心肌免受 MI 诱导的凋亡。与对照组相比，miR-1-ES 细胞和 ES 细胞移植组的间质和血管纤维化明显减少。然而，miR-1-ES 细胞组和 ES 细胞组之间没有统计学意义。最后，MI 后接受 miR-1-ES 细胞移植的小鼠心脏功能明显改善（P < 0.05）。我们的数据表明，miR-1 驱动来自移植的 ES 细胞的心肌细胞分化，并抑制 MI 后的凋亡，最终导致增强的心脏修复、再生和功能。
