Hosoyama Tohru, Samura Makoto, Kudo Tomoaki, Nishimoto Arata, Ueno Koji, Murata Tomoaki, Ohama Takashi, Sato Koichi, Mikamo Akihito, Yoshimura Koichi, Li Tao-Sheng, Hamano Kimikazu
Department of Surgery and Clinical Science, Yamaguchi University Graduate School of MedicineUbe, Japan; Center for Regenerative Medicine, Yamaguchi University Graduate School of MedicineUbe, Japan.
Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine Ube, Japan.
Am J Transl Res. 2015 Dec 15;7(12):2738-51. eCollection 2015.
Cardiosphere-derived cells (CDCs) isolated from postnatal heart tissue are a convenient and efficientresource for the treatment of myocardial infarction. However, poor retention of CDCs in infarcted hearts often causes less than ideal therapeutic outcomes. Cell sheet technology has been developed as a means of permitting longer retention of graft cells, and this therapeutic strategy has opened new avenues of cell-based therapy for severe ischemic diseases. However, there is still scope for improvement before this treatment can be routinely applied in clinical settings. In this study, we investigated whether hypoxic preconditioning enhances the therapeutic efficacy of CDC monolayer sheets. To induce hypoxia priming, CDC monolayer sheets were placed in an incubator adjusted to 2% oxygen for 24 hours, and then preconditioned mouse CDC sheets were implanted into the infarcted heart of old myocardial infarction mouse models. Hypoxic preconditioning of CDC sheets remarkably increased the expression of vascular endothelial growth factor through the PI3-kinase/Akt signaling pathway. Implantation of preconditioned CDC sheets improved left ventricular function inchronically infarcted hearts and reduced fibrosis. The therapeutic efficacy of preconditioned CDC sheets was higher than the CDC sheets that were cultured under normaxia condition. These results suggest that hypoxic preconditioning augments the therapeutic angiogenic and anti-fibrotic activity of CDC sheets. A combination of cell sheets and hypoxic preconditioning offers an attractive therapeutic protocol for CDC transplantation into chronically infarcted hearts.
从出生后心脏组织中分离出的心肌球衍生细胞（CDCs）是治疗心肌梗死的一种便捷且有效的资源。然而，CDCs在梗死心脏中的留存率较低，常常导致治疗效果不尽人意。细胞片技术已被开发出来，作为一种使移植细胞留存时间更长的方法，这种治疗策略为严重缺血性疾病的细胞治疗开辟了新途径。然而，在这种治疗方法能够常规应用于临床之前，仍有改进的空间。在本研究中，我们调查了低氧预处理是否能增强CDC单层片的治疗效果。为诱导低氧预处理，将CDC单层片置于调整为2%氧气的培养箱中24小时，然后将预处理的小鼠CDC片植入老年心肌梗死小鼠模型的梗死心脏中。CDC片的低氧预处理通过PI3激酶/Akt信号通路显著增加了血管内皮生长因子的表达。植入预处理的CDC片改善了慢性梗死心脏的左心室功能并减少了纤维化。预处理的CDC片的治疗效果高于在正常氧条件下培养的CDC片。这些结果表明，低氧预处理增强了CDC片的治疗性血管生成和抗纤维化活性。细胞片与低氧预处理相结合为将CDC移植到慢性梗死心脏中提供了一种有吸引力的治疗方案。
