Human embryonic stem cell-derived cardiac progenitors for severe heart failure treatment: first clinical case report
Human embryonic stem cell-derived cardiac progenitors for severe heart failure treatment: first clinical case report
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DOI：
10.1093/eurheartj/ehv189
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发表时间：
2015-08-07
影响因子：
39.3
通讯作者：
Larghero, Jerome
中科院分区：
文献类型：
--
作者：
Menasche, Philippe;Vanneaux, Valerie;Larghero, Jerome
目的比较研究表明，致力于心脏谱系的干细胞比具有心外表型的干细胞更有效地改善心脏功能。因此，我们已经开发了一个人口的人胚胎干细胞（ESC）衍生的心脏祖细胞。方法和结果未分化的人胚胎干细胞（I6线）进行扩增和心脏承诺通过暴露于骨形态发生蛋白-2和成纤维细胞生长因子受体抑制剂。响应于这些心脏指导性线索的细胞表达心脏转录因子Isl-1和阶段特异性胚胎抗原SSEA-1，然后将其用于通过免疫磁性分选来纯化它们。然后将Isl-1（+）SSEA-1（+）细胞包埋到纤维蛋白支架中，将其通过手术递送到患有严重心力衰竭的68岁患者的梗塞区域[纽约心脏协会[NYHA]功能III级;左心室射血分数（LVEF）：26%]。同时在非梗死区域进行冠状动脉搭桥术。植入的细胞具有高纯度（99%为SSEA-1（+）），失去了作为多能性标志物的Sox-2和Nanog的表达，并强烈表达Isl-1。补片的术中输送迅速。术后病程也不复杂。3个月后，患者的心功能得到改善（NYHA功能I级; LVEF：36%），并且在先前无动力细胞/贴片治疗的非血运重建区域中，超声心动图显示新发收缩性明显。有没有并发症，如心律失常，肿瘤形成，或免疫抑制相关的不良事件。结论这一观察表明，产生一个临床级人口的人胚胎干细胞衍生的心脏祖细胞，并结合它在一个组织工程构建的可行性。虽然任何关于疗效的结论都是毫无意义的，但患者的功能结果提供了一个令人鼓舞的提示。除此之外，已经设置的平台可以用于产生不同的ESC衍生的谱系特异性后代。
Aims Comparative studies suggest that stem cells committed to a cardiac lineage are more effective for improving heart function than those featuring an extra-cardiac phenotype. We have therefore developed a population of human embryonic stem cell (ESC)-derived cardiac progenitor cells.Methods and results Undifferentiated human ESCs (I6 line) were amplified and cardiac-committed by exposure to bone morphogenetic protein-2 and a fibroblast growth factor receptor inhibitor. Cells responding to these cardio-instructive cues express the cardiac transcription factor Isl-1 and the stage-specific embryonic antigen SSEA-1 which was then used to purify them by immunomagnetic sorting. The Isl-1(+) SSEA-1(+) cells were then embedded into a fibrin scaffold which was surgically delivered onto the infarct area in a 68-year-old patient suffering from severe heart failure [New York Heart Association [NYHA] functional Class III; left ventricular ejection fraction (LVEF): 26%]. A coronary artery bypass was performed concomitantly in a non-infarcted area. The implanted cells featured a high degree of purity (99% were SSEA-1(+)), had lost the expression of Sox-2 and Nanog, taken as markers for pluripotency, and strongly expressed Isl-1. The intraoperative delivery of the patch was expeditious. The post-operative course was uncomplicated either. After 3 months, the patient is symptomatically improved (NYHA functional Class I; LVEF: 36%) and a new-onset contractility is echocardiographically evident in the previously akinetic cell/patch-treated, non-revascularized area. There have been no complications such as arrhythmias, tumour formation, or immunosuppression-related adverse events.Conclusion This observation demonstrates the feasibility of generating a clinical-grade population of human ESC-derived cardiac progenitors and combining it within a tissue-engineered construct. While any conclusion pertaining to efficacy would be meaningless, the patient's functional outcome yet provides an encouraging hint. Beyond this case, the platform that has been set could be useful for generating different ESC-derived lineage-specific progenies.