In this work, we investigated the in vitro and in vivo functions of bisphosphonate of zoledronate (Zd) in hypoxia/reoxygenation (H/R) injured human embryonic stem cell-derived cardiomyocytes (hES-CMs). In the in vitro setting, the effects of Zd on hES-CM survival and differentiation were examined. We found that low and medium concentrations (<2 µm) of Zd did not induce cell death of hES-CMs. 0.5 µm Zd protected H/R-induced hES-CM apoptosis but did not affect key differentiation proteins, including hcTnl, PECM-1 Cnx43 and Pan-Cadherin. In addition, Zd-induced TrkA/B phosphorylation and promoted VEGF to counter the apoptotic effect of H/R injury. In the in vivo animal model of myocardial infarction, Zd treatment promoted the survival of hES-CMs by inducing PECAM1 and hcTnl. Thus, we concluded that Zd protected H/R-induced hES-CM apoptosis in vitro and promoted hES-CM survival in vivo. These data may facilitate the development of human embryonic stem cells into clinical applications for patients with ischemic heart disease.

在这项工作中，我们研究了唑来膦酸二膦酸盐 (Zd) 在缺氧/复氧 (H/R) 损伤的人胚胎干细胞衍生心肌细胞 (hES-CMs) 中的体外和体内功能。在体外环境中，检查了 Zd 对 hES-CM 存活和分化的影响。我们发现低和中等浓度 (<2 µm) 的 Zd 不会诱导 hES-CM 的细胞死亡。0.5 µm Zd 可保护 H/R 诱导的 hES-CM 细胞凋亡，但不影响关键分化蛋白，包括 hcTnl、PECM-1 Cnx43 和 Pan-Cadherin。此外，Zd 诱导 TrkA/B 磷酸化并促进 VEGF 对抗 H/R 损伤的细胞凋亡作用。在心肌梗死的体内动物模型中，Zd 治疗通过诱导 PECAM1 和 hcTnl 促进 hES-CMs 的存活。因此，我们得出结论，Zd 在体外保护 H/R 诱导的 hES-CM 细胞凋亡并在体内促进 hES-CM 存活。这些数据可能有助于将人类胚胎干细胞发展到缺血性心脏病患者的临床应用中。