Gong Xuhe, Wang Pengbo, Wu Qingqing, Wang Sijia, Yu Litian, Wang Guogan
Emergency and Critical Center, Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China.
Departments of Obstetrics and Gynaecology, Fuxing Hospital, Capital Medical University, Beijing, China.
Eur J Cell Biol. 2016 Jan;95(1):57-67. doi: 10.1016/j.ejcb.2015.11.003. Epub 2015 Nov 21.
Cell transplantation is a promising strategy in regenerative medicine. Beneficial effects of bone marrow mesenchymal stem cells (BM-MSCs) on heart disease have been widely reported. However, the MSCs in these studies have been mainly derived from autologous animals, and data on MSCs from human umbilical cord blood (UCB-MSCs) are still scarce. We investigated whether intramyocardial xenogeneic administration of UCB-MSCs is beneficial for preserving heart function in a cTnT(R141W) transgenic mouse of dilated cardiomyopathy (DCM). Cultured UCB-MSCs, which were identified by there morphology, differentiation and cell surface markers, were transplanted into cTnT(R141W) transgenic mice to examine apoptosis, fibrosis, vasculogenesis and the associated Akt pathway. Moreover, we measured the expression levels of VEGF and IGF-1, which are growth factors required for differentiation into cardiomyocytes, and are also involved in cardiac regeneration and improving heart function. One month after transplantation, MSCs significantly decreased chamber dilation and contractile dysfunction in the cTnT(R141W) mice. MSCs transplanted hearts showed a significant decrease in cardiac apoptosis and its regulation by the Akt pathway. Cardiac fibrosis and cytoplasmic vacuolisation were significantly attenuated in the MSCs group. Importantly, the levels of VEGF and IGF-1 were increased in the MSCs transplanted hearts. In vitro, the MSC-conditioned medium displayed anti-apoptotic activity in h9c2 cardiomyocytes subjected to hypoxia. These results further confirm the paracrine effects of MSCs. In conclusion, UCB-MSCs preserve cardiac function after intramyocardial transplantation in a DCM mouse, and this effect may be associated with reductions in cellular apoptosis, inflammation, hypertrophy and myocardial fibrosis; in addition to; up-regulation of Akt, VEGF and IGF-1; and enhanced angiogenesis.
细胞移植是再生医学中一种很有前景的策略。骨髓间充质干细胞（BM-MSCs）对心脏病的有益作用已被广泛报道。然而，这些研究中的间充质干细胞主要来源于自体动物，而关于人脐带血间充质干细胞（UCB-MSCs）的数据仍然很少。我们研究了心肌内异种移植UCB-MSCs是否有利于在cTnT（R141W）扩张型心肌病（DCM）转基因小鼠中保留心脏功能。将通过形态、分化和细胞表面标志物鉴定的培养UCB-MSCs移植到cTnT（R141W）转基因小鼠中，以检测细胞凋亡、纤维化、血管生成及相关的Akt信号通路。此外，我们测量了VEGF和IGF-1的表达水平，它们是分化为心肌细胞所需的生长因子，也参与心脏再生和改善心脏功能。移植后一个月，间充质干细胞显著减少了cTnT（R141W）小鼠的心室扩张和收缩功能障碍。移植间充质干细胞的心脏显示出心脏细胞凋亡及其通过Akt信号通路的调节显著减少。间充质干细胞组的心脏纤维化和细胞质空泡化显著减轻。重要的是，移植间充质干细胞的心脏中VEGF和IGF-1的水平升高。在体外，间充质干细胞条件培养基在缺氧的h9c2心肌细胞中显示出抗凋亡活性。这些结果进一步证实了间充质干细胞的旁分泌作用。总之，UCB-MSCs在DCM小鼠心肌内移植后可保留心脏功能，这种作用可能与细胞凋亡、炎症、肥大和心肌纤维化的减少有关；此外还与Akt、VEGF和IGF-1的上调以及血管生成增强有关。
