Small molecules are widely used to induce stem cell differentiation. 2'-deoxycytidine (2-DC) belongs to the cytidine family. It stimulates the expression of cardiac-specific genes and proteins, and directs mesenchymal stem cells towards cardiomyogenic differentiation. We aim to investigate the role of 2-DC-treated human umbilical cord mesenchymal stem cells (UC-MSCs) into myogenic lineage and explore their application in regeneration of infarcted myocardium. UC-MSCs were treated with 5, 10, 20, and 40 µM 2-DC following optimization by cytotoxicity analysis. Rat model of myocardial infarction (MI) was induced by ligating left anterior descending coronary artery. Normal, and 2-DC treated UC-MSCs were transplanted in the left ventricular wall immediately after ligation. Echocardiographic measurements were performed to assess cardiac function. Tissue architecture of the myocardium was examined by histological analysis to determine fate of the transplanted cells. MSCs were successfully isolated from human umbilical cord tissue. 2-DC treatment did not produce any significant cytotoxic effect in UC-MSCs at all concentrations. qPCR analysis of treated UC-MSCs showed induction of myogenic differentiation, which is more pronounced at 20 μM concentration. Fluorescently labeled 2-DC-treated UC-MSCs showed significant (**P < 0.01) homing in the infarcted myocardium as compared to normal UC-MSCs. Hearts transplanted with 2-DC-treated UC-MSCs significantly (***P < 0.001) improved the cardiac systolic and diastolic functions and pumping ability as compared to normal UC-MSCs and MI groups. Fibrotic area and left ventricular wall thickness were significantly improved (***P < 0.001) in 2-DC-treated group as compared to normal UC-MSCs. Immunohistochemical staining showed co-localization of fluorescently labeled cells and patches of differentiated myocytes which were stained for cardiac proteins in the infarct zone implying that the treated UC-MSCs regenerated cardiomyocytes. We report for the first time that 2-DC induces cardiac differentiation in UC-MSCs. Transplanted cells differentiated into functional cardiomyocytes and significantly improved cardiac performance. These pre-differentiated cardiac progenitors showed better survival, homing, and distribution in the infarcted zone. 2-DC treated cells not only improved cardiac function, but also restored tissue homeostasis, suggesting a better therapeutic option for the regeneration of cardiac tissue in the clinical setup.

中文翻译：

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小分子2'-脱氧胞苷在体外将人脐带间充质干细胞分化为心脏祖细胞，其体内异种移植改善了心脏功能。

小分子被广泛用于诱导干细胞分化。2'-脱氧胞苷（2-DC）属于胞苷家族。它刺激心脏特异性基因和蛋白质的表达，并指导间充质干细胞向心肌分化。我们旨在调查2-DC处理的人脐带间充质干细胞（UC-MSCs）在成肌谱系中的作用，并探讨其在梗死心肌再生中的应用。通过细胞毒性分析优化后，用5、10、20和40 µM 2-DC处理UC-MSC。结扎左冠状动脉前降支，建立大鼠心肌梗死模型。结扎后立即将正常和2-DC处理的UC-MSC移植到左心室壁中。进行超声心动图测量以评估心脏功能。通过组织学分析检查心肌的组织结构，以确定移植细胞的命运。从人脐带组织中成功分离了MSC。在所有浓度下，2-DC处理均未在UC-MSC中产生任何明显的细胞毒性作用。经处理的UC-MSC的qPCR分析显示诱导了肌原性分化，在20μM浓度下更为明显。与正常的UC-MSC相比，荧光标记的2-DC处理的UC-MSC在梗死的心肌中显示出显着的归巢（** P <0.01）。与正常的UC-MSC和MI组相比，经2-DC处理的UC-MSC移植的心脏显着改善了心脏的收缩和舒张功能以及泵动能力。纤维化面积和左心室壁厚度显着改善（*** P <0。与正常的UC-MSC相比，2-DC处理组的001）。免疫组织化学染色显示荧光标记的细胞和分化的心肌细胞的斑块共定位，这些心肌斑块在梗死区被心脏蛋白染色，这表明处理过的UC-MSCs再生了心肌细胞。我们首次报道2-DC诱导UC-MSCs的心脏分化。移植的细胞分化为功能性心肌细胞，并显着改善心脏性能。这些预分化的心脏祖细胞在梗死区表现出更好的生存，归巢和分布。2-DC处理的细胞不仅改善了心脏功能，而且还恢复了组织稳态，这为临床设置中再生心脏组织提供了更好的治疗选择。免疫组织化学染色显示荧光标记的细胞和分化的心肌细胞的斑块共定位，这些心肌斑块在梗死区被心脏蛋白染色，这表明处理过的UC-MSCs再生了心肌细胞。我们首次报道2-DC诱导UC-MSCs的心脏分化。移植的细胞分化为功能性心肌细胞，并显着改善心脏性能。这些预分化的心脏祖细胞在梗死区表现出更好的生存，归巢和分布。2-DC处理的细胞不仅改善了心脏功能，而且还恢复了组织的动态平衡，这为临床设置中的心脏组织再生提供了更好的治疗选择。免疫组织化学染色显示荧光标记的细胞和分化的心肌细胞的斑块共定位，这些心肌斑块在梗死区被心脏蛋白染色，这表明处理过的UC-MSCs再生了心肌细胞。我们首次报道2-DC诱导UC-MSCs的心脏分化。移植的细胞分化为功能性心肌细胞，并显着改善心脏性能。这些预分化的心脏祖细胞在梗死区表现出更好的生存，归巢和分布。2-DC处理的细胞不仅改善了心脏功能，而且还恢复了组织稳态，这为临床设置中再生心脏组织提供了更好的治疗选择。