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首页> 美国卫生研究院文献>APL Bioengineering >Modelling ischemia-reperfusion injury (IRI) in vitro using metabolically matured induced pluripotent stem cell-derived cardiomyocytes
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Modelling ischemia-reperfusion injury (IRI) in vitro using metabolically matured induced pluripotent stem cell-derived cardiomyocytes

机译：使用代谢成熟的诱导多能干细胞衍生的心肌细胞体外模拟缺血再灌注损伤（IRI）

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Coronary intervention following ST-segment elevation myocardial infarction (STEMI) is the treatment of choice for reducing cardiomyocyte death but paradoxically leads to reperfusion injury. Pharmacological post-conditioning is an attractive approach to minimize Ischemia-Reperfusion Injury (IRI), but candidate drugs identified in IRI animal models have performed poorly in human clinical trials, highlighting the need for a human cell-based model of IRI. In this work, we show that when we imposed sequential hypoxia and reoxygenation episodes [mimicking the ischemia (I) and reperfusion (R) events] to immature human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs), they display significant hypoxia resistance and minimal cell death (∼5%). Metabolic maturation of hPSC-CMs for 8 days substantially increased their sensitivity to changes in oxygen concentration and led to up to ∼30% cell death post-hypoxia and reoxygenation. To mimic the known transient changes in the interstitial tissue microenvironment during an IRI event in vivo, we tested a new in vitro IRI model protocol that required glucose availability and lowering of media pH during the ischemic episode, resulting in a significant increase in cell death in vitro (∼60%). Finally, we confirm that in this new physiologically matched IRI in vitro model, pharmacological post-conditioning reduces reperfusion-induced hPSC-CM cell death by 50%. Our results indicate that in recapitulating key aspects of an in vivo IRI event, our in vitro model can serve as a useful method for the study of IRI and the validation and screening of human specific pharmacological post-conditioning drug candidates.
机译：ST段抬高型心肌梗死（STEMI）后进行冠状动脉介入治疗是减少心肌细胞死亡的首选治疗方法，但自相矛盾地会导致再灌注损伤。药理学后处理是一种将缺血再灌注损伤（IRI）降至最低的有吸引力的方法，但是在IRI动物模型中鉴定出的候选药物在人类临床试验中表现不佳，从而凸显了对基于人细胞的IRI模型的需求。在这项工作中，我们表明，当对未成熟的人类多能干细胞衍生的心肌细胞（hPSC-CM）施加顺序的缺氧和复氧发作（模仿缺血（I）和再灌注（R）事件）时，它们表现出显着的缺氧抵抗力，最小的细胞死亡（〜5％）。 hPSC-CMs的代谢成熟期为8天，大大提高了其对氧浓度变化的敏感性，并导致缺氧和复氧后细胞死亡高达30％。为了模拟体内IRI事件期间间质组织微环境的已知瞬时变化，我们测试了一种新的体外IRI模型方案，该方案要求在缺血发作期间提供葡萄糖并降低培养基pH，从而导致细胞死亡显着增加。体外（〜60％）。最后，我们确认在这种新的生理匹配IRI体外模型中，药理学后处理可将再灌注诱导的hPSC-CM细胞死亡减少50％。我们的结果表明，在概括体内IRI事件的关键方面时，我们的体外模型可以作为研究IRI以及验证和筛选人特异性药理后调节候选药物的有用方法。

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