Human Cardiac Stem Cells With Reduced Notch Signaling Show Enhanced Therapeutic Potential in a Rat Acute Infarction Model
Human Cardiac Stem Cells With Reduced Notch Signaling Show Enhanced Therapeutic Potential in a Rat Acute Infarction Model
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DOI：
10.1253/circj.cj-13-0534
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发表时间：
2014-01-01
影响因子：
3.3
通讯作者：
Sawa, Yoshiki
中科院分区：
文献类型：
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作者：
Matsuda, Takenori;Miyagawa, Shigeru;Sawa, Yoshiki
工作背景：由于人类心脏干细胞（CSC）在受损的心脏组织中具有再生潜力，因此将其用于心力衰竭的细胞治疗越来越受到关注。然而，扩增CSC同时保持其治疗潜力的培养条件尚未优化。我们假设接种细胞密度会通过Notch信号通路影响CSCs的增殖活性、分化和治疗潜力。在体外检测细胞群体倍增时间、C-KIT阳性率和地塞米松诱导的多向分化潜能。通过将CSCs移植到大鼠急性心肌梗死（AMI）模型中来评估CSCs的治疗潜力。低密度培养（340 cells/cm 2）可维持细胞的多向分化潜能，并具有较高的体外增殖活性和C-KIT阳性率。另一方面，高接种密度（5，500个细胞/cm（2））通过激活Notch信号在体外诱导自主分化为内皮细胞。与高密度培养的CSC相比，在Notch信号抑制剂的作用下，低密度或高密度培养的CSC在体内显示出更大的治疗潜力。结论：在大鼠AMI模型中，在Notch信号抑制剂的作用下，培养的CSC显示出更好的心肌分化和治疗潜力。因此，当培养CSC用于临床应用时，减少Notch信号传导是重要的。
Background: Because human cardiac stem cells (CSC) have regeneration potential in damaged cardiac tissue, there is increasing interest in using them in cell-based therapies for cardiac failure. However, culture conditions, by which CSCs are expanded while maintaining their therapeutic potential, have not been optimized. We hypothesized that the plating cell-density would affect proliferation activity, differentiation and therapeutic potential of CSCs through the Notch signaling pathway.Methods and Results: Human CSCs were plated at 4 different densities. The population doubling time, C-KIT positivity, and dexamethasone-induced multidifferentiation potential were examined in vitro. The therapeutic potential of CSCs was assessed by transplanting them into a rat acute myocardial infarction (AMI) model. The low plating density (340 cells/cm(2)) maintained the multidifferentiation potential with greater proliferation activity and C-KIT positivity in vitro. On the other hand, the high plating density (5,500 cells/cm(2)) induced autonomous differentiation into endothelial cells by activating Notch signaling in vitro. CSCs cultured at low or high density with Notch signal inhibitor showed significantly greater therapeutic potential in vivo compared with those cultured at high density.Conclusions: CSCs cultured with reduced Notch signaling showed better cardiomyogenic differentiation and therapeutic potentials in a rat AMI model. Thus, reducing Notch signaling is important when culturing CSCs for clinical applications.