Sonic hedgehog-modified human CD34+ cells preserve cardiac function after acute myocardial infarction.
Sonic hedgehog-modified human CD34+ cells preserve cardiac function after acute myocardial infarction.
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DOI：
10.1161/circresaha.112.266015
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发表时间：
2012-07-20
影响因子：
20.1
通讯作者：
Losordo DW
中科院分区：
文献类型：
--
作者：
Mackie AR;Klyachko E;Thorne T;Schultz KM;Millay M;Ito A;Kamide CE;Liu T;Gupta R;Sahoo S;Misener S;Kishore R;Losordo DW
缺血性心血管疾病是目前人口老龄化面临的最大流行病之一。目前的文献已经说明了自体干细胞疗法作为治疗这些疾病的新策略的有效性。CD34+造血干细胞通过促进血管生成，帮助保存缺血心肌的功能，在治疗心肌缺血方面显示出巨大的前景。不幸的是，随着年龄的增加和心血管健康状况的恶化，自体CD34+细胞的活性和血管生成质量都会下降。为了抵消年龄和健康相关的CD34+细胞血管生成减少的影响，我们探索了是否可以通过增加人CD34+细胞分泌已知的血管生成因子Sonic Hedgehog(Shh)来增强其治疗效果。当将Shh修饰的CD34+细胞(CD34Shh)注射到小鼠急性心肌梗死(AMI)后的交界区时，可防止与AMI相关的脑室扩张和心功能下降。与未修饰的CD34细胞或转染空载体的细胞相比，CD34Shh治疗还缩小了梗塞面积，增加了边缘区毛细血管密度。CD34Shh主要在外体中存储和分泌Shh蛋白，这种存储过程似乎是细胞类型特有的。对CD34Shh来源的外切体的体外分析表明：1)外切体将Shh蛋白转移到其他类型的细胞，2)功能性Shh的外切体转移在受体细胞中诱导了规范的Shh信号通路。外切体介导的Shh传递到缺血心肌是CD34Shh细胞治疗的小鼠观察到的心功能保留的主要机制。
Ischemic cardiovascular disease represents one of the largest epidemics currently facing the aging population. Current literature has illustrated the efficacy of autologous, stem cell therapies as novel strategies for treating these disorders. The CD34+ hematopoetic stem cell has shown significant promise in addressing myocardial ischemia by promoting angiogenesis that helps preserve the functionality of ischemic myocardium. Unfortunately, both viability and angiogenic quality of autologous CD34+ cells decline with advanced age and diminished cardiovascular health. To offset age and health-related angiogenic declines in CD34+ cells, we explored whether the therapeutic efficacy of human CD34+ cells could be enhanced by augmenting their secretion of the known angiogenic factor, sonic hedgehog (Shh). When injected into the border zone of mice following acute myocardial infarction (AMI), Shh-modified CD34+ cells (CD34Shh) protected against ventricular dilation and cardiac functional declines associated with AMI. Treatment with CD34Shh also reduced infarct size and increased border zone capillary density compared to unmodified CD34 cells or cells transfected with the empty vector. CD34Shh primarily store and secrete Shh protein in exosomes and this storage process appears to be cell-type specific. In vitro analysis of exosomes derived from CD34Shh revealed that; 1) exosomes transfer Shh protein to other cell types and, 2) exosomal transfer of functional Shh elicits induction of the canonical Shh signaling pathway in recipient cells. Exosome-mediated delivery of Shh to ischemic myocardium represents a major mechanism explaining the observed preservation of cardiac function in mice treated with CD34Shh cells.