BACKGROUND Parthenogenetic stem cells (PSCs) are a promising source of regenerated cardiomyocytes; however, their application may be limited without a paternal genome. Insulin-like growth factor-II (IGF-II), a paternally expressed growth hormone, is critical in embryonic differentiation. This study investigated whether forced expression of IGF-II in PSCs can accelerate their differentiation. METHODS Overexpression and re-knockdown of IGF-II in PSCs were performed to investigate the role of IGF-II in PSC differentiation. The derivatives of PSCs with different IGF-II manipulations were transplanted into infarcted murine hearts to investigate the role of IGF-II in cardiomyocyte differentiation in vivo. RESULTS Data showed that the expression of cardiac troponin T and troponin I in IGF-II-PSC outgrowths preceded that of parental PSC outgrowths, suggesting that IGF-II can accelerate PSC differentiation into cardiac lineage. Overexpression of IGF-II accelerated PSC differentiation towards cardiomyocytes while inhibiting PSC proliferation via the IGF-II/IGF1R signaling. Similar to that observed in cardiac marker expression, on differentiation day 24, IGF-II-PSCs showed PCNA and cyclin D2 expression comparable to juvenile mouse cardiomyocytes, showing that IGF-II-PSCs at this stage possess differential and proliferative properties similar to those of juvenile cardiomyocytes. Moreover, the expression pattern of cardiac markers in IGF-II-overexpressing PSC derivatives resembled that of juvenile mouse cardiomyocytes. After transplantation into the infarcted mouse hearts, IGF-II-PSC-derived cardiomyocytes displayed significant characteristics of mature cardiomyocytes, and IGF-II-depletion by shRNA significantly reversed these effects, suggesting the critical role of IGF-II in promoting cardiomyocyte maturation in vivo. Furthermore, IGF-II-overexpressing PSC derivatives reduced collagen deposition and mitochondrial damage in the infarcted areas and improved cardiac function. The re-knockdown of IGF-II could counteract these favorable effects of IGF-II. CONCLUSIONS These findings suggest that the ectopic expression of IGF-II accelerates PSC differentiation into the cardiac lineage and promotes cardiomyocyte maturation. The underlying process includes the IGF-II/IGF1R signaling, which is involved in the suppressive effect of IGF-II on PSC proliferation. Moreover, transplanting IGF-II-overexpressing PSC derivatives into the infarcted heart could reduce collagen deposition and improve mitochondria biogenesis and measurements of cardiac function, highlighting the importance of IGF-II in the application of PSCs in cardiac regeneration.

中文翻译：

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胰岛素样生长因子-II 过表达加速孤雌生殖干细胞分化为心肌细胞并改善小鼠急性心肌梗死后的心脏功能。

背景孤雌生殖干细胞（PSCs）是再生心肌细胞的有希望的来源。然而，如果没有父系基因组，它们的应用可能会受到限制。胰岛素样生长因子-II (IGF-II) 是一种父系表达的生长激素，对胚胎分化至关重要。本研究调查了 IGF-II 在 PSC 中的强制表达是否可以加速它们的分化。方法 在 PSC 中过表达和重新敲除 IGF-II 以研究 IGF-II 在 PSC 分化中的作用。将具有不同 IGF-II 操作的 PSC 衍生物移植到梗塞的小鼠心脏中，以研究 IGF-II 在体内心肌细胞分化中的作用。结果 数据显示，IGF-II-PSC 产物中心肌肌钙蛋白 T 和肌钙蛋白 I 的表达先于亲本 PSC 产物的表达，表明 IGF-II 可以加速 PSC 分化为心脏谱系。IGF-II 的过表达加速 PSC 向心肌细胞的分化，同时通过 IGF-II/IGF1R 信号抑制 PSC 增殖。与在心脏标志物表达中观察到的相似，在分化第 24 天，IGF-II-PSCs 的 PCNA 和 cyclin D2 表达与幼年小鼠心肌细胞相当，表明该阶段的 IGF-II-PSCs 具有与幼年心肌细胞。此外，过表达 IGF-II 的 PSC 衍生物中心脏标志物的表达模式类似于幼年小鼠心肌细胞的表达模式。移植到梗塞小鼠心脏后，IGF-II-PSC衍生的心肌细胞表现出成熟心肌细胞的显着特征，并且 shRNA 消耗 IGF-II 显着逆转了这些作用，表明 IGF-II 在促进体内心肌细胞成熟中的关键作用。此外，过表达 IGF-II 的 PSC 衍生物减少了梗塞区域的胶原沉积和线粒体损伤，并改善了心脏功能。重新敲除 IGF-II 可以抵消 IGF-II 的这些有利影响。结论 这些发现表明，IGF-II 的异位表达加速 PSC 分化为心脏谱系并促进心肌细胞成熟。潜在的过程包括 IGF-II/IGF1R 信号传导，其参与 IGF-II 对 PSC 增殖的抑制作用。而且，