Departments of Anesthesia and Medicine, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis St., Boston, MA 02115, USA.
Circulation. 2011 Mar 29;123(12):1287-96. doi: 10.1161/CIRCULATIONAHA.110.982918. Epub 2011 Mar 14.
Cardiac stem cells (CSCs) delivered to the infarcted heart generate a large number of small fetal-neonatal cardiomyocytes that fail to acquire the differentiated phenotype. However, the interaction of CSCs with postmitotic myocytes results in the formation of cells with adult characteristics.
On the basis of results of in vitro and in vivo assays, we report that the commitment of human CSCs (hCSCs) to the myocyte lineage and the generation of mature working cardiomyocytes are influenced by microRNA-499 (miR-499), which is barely detectable in hCSCs but is highly expressed in postmitotic human cardiomyocytes. miR-499 traverses gap junction channels and translocates to structurally coupled hCSCs favoring their differentiation into functionally competent cells. Expression of miR-499 in hCSCs represses the miR-499 target genes Sox6 and Rod1, enhancing cardiomyogenesis in vitro and after infarction in vivo. Although cardiac repair was detected in all cell-treated infarcted hearts, the aggregate volume of the regenerated myocyte mass and myocyte cell volume were greater in animals injected with hCSCs overexpressing miR-499. Treatment with hCSCs resulted in an improvement in ventricular function, consisting of a better preservation of developed pressure and positive and negative dP/dt after infarction. An additional positive effect on cardiac performance occurred with miR-499, pointing to enhanced myocyte differentiation/hypertrophy as the mechanism by which miR-499 potentiated the restoration of myocardial mass and function in the infarcted heart.
The recognition that miR-499 promotes the differentiation of hCSCs into mechanically integrated cardiomyocytes has important clinical implications for the treatment of human heart failure.
移植到梗死心脏的心脏干细胞（CSC）产生大量未能获得分化表型的小胎儿-新生儿心肌细胞。然而，CSC 与有丝分裂后心肌细胞的相互作用导致形成具有成人心肌细胞特征的细胞。
基于体外和体内实验的结果，我们报告说，人 CSC（hCSC）向心肌谱系的定向分化和成熟工作心肌细胞的生成受 microRNA-499（miR-499）的影响，miR-499 在 hCSC 中几乎检测不到，但在有丝分裂后人类心肌细胞中高度表达。miR-499 通过缝隙连接通道转运，并易位到结构偶联的 hCSC 中，有利于其分化为功能上成熟的细胞。miR-499 在 hCSC 中的表达抑制了 miR-499 的靶基因 Sox6 和 Rod1，增强了体外心肌发生和体内梗死后的心肌发生。尽管在所有接受细胞治疗的梗死心脏中都检测到了心脏修复，但在注射过表达 miR-499 的 hCSC 的动物中，再生心肌细胞质量和心肌细胞体积的总和更大。hCSC 治疗导致心室功能改善，表现为梗死后发展压和正负 dp/dt 的更好保留。miR-499 产生了额外的对心脏功能的积极影响，表明 miR-499 增强了心肌细胞分化/肥大，这是 miR-499 增强梗死心脏心肌质量和功能恢复的机制。
miR-499 促进 hCSC 分化为机械整合的心肌细胞的认识对人类心力衰竭的治疗具有重要的临床意义。
