Transplantation of cardiac progenitor cells ameliorates cardiac dysfunction after myocardial infarction in mice
Transplantation of cardiac progenitor cells ameliorates cardiac dysfunction after myocardial infarction in mice
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DOI：
10.1172/jci37456
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发表时间：
2009-08-01
影响因子：
15.9
通讯作者：
Komuro, Issei
中科院分区：
文献类型：
--
作者：
Matsuura, Katsuhisa;Honda, Atsushi;Komuro, Issei
心脏祖细胞是心力衰竭细胞治疗的潜在来源。尽管最近的研究表明心脏干/祖细胞移植可以改善梗塞心脏的功能，但功能改善的确切机制仍然知之甚少。本研究表明，移植克隆扩增的干细胞抗原 1 阳性（Sca-1 阳性）细胞 (CPC) 可改善小鼠心肌梗塞后的心功能障碍。 CPC有效分化为心肌细胞并分泌多种细胞因子，包括可溶性VCAM-1（sVCAM-1）。分泌的 sVCAM-1 诱导内皮细胞和 CPC 迁移，并通过激活 Akt、ERK 和 p38 MAPK 防止心肌细胞因氧化应激而死亡。使用针对 sVCAM-1 受体极晚期抗原 4 (VLA-4) 的特异性抗体进行治疗，可消除 CPC 衍生条件培养基对体外心肌细胞和 CPC 的影响，并抑制体内血管生成、CPC 迁移和存活，从而导致 CPC 片移植后改善的心脏功能减弱。这些结果表明 CPC 移植可改善心脏功能。心肌梗死后，通过 sVCAM-1/VLA-4 信号通路介导的心肌细胞分化和旁分泌机制。
Cardiac progenitor cells are a potential source of cell therapy for heart failure. Although recent studies have shown that transplantation of cardiac stem/progenitor cells improves function of infarcted hearts, the precise mechanisms of the improvement in function remain poorly understood. The present study demonstrates that transplantation of sheets of clonally expanded stem cell antigen 1-positive (Sca-1-positive) cells (CPCs) ameliorates cardiac dysfunction after myocardial infarction in mice. CPC efficiently differentiated into cardiomyocytes and secreted various cytokines, including soluble VCAM-1 (sVCAM-1). Secreted sVCAM-1 induced migration of endothelial cells and CPCs and prevented cardiomyocyte death from oxidative stress through activation of Akt, ERK, and p38 MAPK. Treatment with antibodies specific for very late antigen-4 (VLA-4), a receptor of sVCAM-1, abolished the effects of CPC-derived conditioned medium on cardiomyocytes and CPCs in vitro and inhibited angiogenesis, CPC migration, and survival in vivo, which led to attenuation of improved cardiac function following transplantation of CPC sheets. These results suggest that CPC transplantation improves cardiac function. after myocardial infarction through cardiomyocyte differentiation and paracrine mechanisms mediated via the sVCAM-1/VLA-4 signaling pathway.