In vitro Models of Ischemia-Reperfusion Injury.
In vitro Models of Ischemia-Reperfusion Injury.
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DOI：
10.1007/s40883-018-0056-0
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发表时间：
2018-09
影响因子：
2.6
通讯作者：
Vunjak-Novakovic G
中科院分区：
文献类型：
--
作者：
Chen T;Vunjak-Novakovic G
心肌梗死后及时再灌注对于挽救缺血区域是必要的；然而，再灌注本身也是最终组织损伤的主要原因。目前，尚无临床相关疗法可用于减少缺血再灌注损伤（IRI）。虽然许多药物在临床前研究中显示出降低 IRI 的前景，但这些药物都没有在大型临床试验中显示出益处。治疗转化失败的部分原因可归因于临床前研究对小动物模型的依赖。虽然动物模型概括了体内系统环境的复杂性，但它们并不能完全概括人类心脏生理学。此外，很难在体内解开各种相互作用的途径。相比之下，使用分离的心肌细胞的体外模型可以研究治疗对心肌细胞的直接影响。可以在模拟缺血再灌注中控制外部因素，以便更好地了解驱动 IRI 的机制。此外，源自人类诱导多能干细胞（hIPS-CM）的心肌细胞的可用性提供了在体外重现人类生理学的机会。不幸的是，hIPS-CM 在表型上相对处于胎儿状态，并且比成熟细胞更能抵抗缺氧。组织工程平台可以促进心肌细胞成熟，以获得更具预测性的生理反应。这些平台可以进一步改进，以考虑临床环境中出现的异质患者群体并促进治疗的转化。因此，可以使用现有工具进一步开发当前的临床前研究，以实现更好的预测药物测试和对 IRI 的理解。在本文中，我们讨论了 IRI 体外建模的最新技术，提出了组织工程在研究 IRI 和测试新治疗方式中的作用，以及人体组织模型如何促进临床转化。
Timely reperfusion after a myocardial infarction is necessary to salvage the ischemic region; however, reperfusion itself is also a major contributor to the final tissue damage. Currently, there is no clinically relevant therapy available to reduce ischemia-reperfusion injury (IRI). While many drugs have shown promise in reducing IRI in preclinical studies, none of these drugs have demonstrated benefit in large clinical trials. Part of this failure to translate therapies can be attributed to the reliance on small animal models for preclinical studies. While animal models encapsulate the complexity of the systemic in vivo environment, they do not fully recapitulate human cardiac physiology. Furthermore, it is difficult to uncouple the various interacting pathways in vivo. In contrast, in vitro models using isolated cardiomyocytes allow studies of the direct effect of therapeutics on cardiomyocytes. External factors can be controlled in simulated ischemia-reperfusion to allow for better understanding of the mechanisms that drive IRI. In addition, the availability of cardiomyocytes derived from human induced pluripotent stem cells (hIPS-CMs) offers the opportunity to recapitulate human physiology in vitro. Unfortunately, hIPS-CMs are relatively fetal in phenotype, and are more resistant to hypoxia than the mature cells. Tissue engineering platforms can promote cardiomyocyte maturation for a more predictive physiologic response. These platforms can further be improved upon to account for the heterogenous patient populations seen in the clinical settings and facilitate the translation of therapies. Thereby, the current preclinical studies can be further developed using currently available tools to achieve better predictive drug testing and understanding of IRI. In this article, we discuss the state of the art of in vitro modeling of IRI, propose the roles for tissue engineering in studying IRI and testing the new therapeutic modalities, and how the human tissue models can facilitate translation into the clinic.