Stern Brett, Monteleone Peter, Zoldan Janet
The University of Texas at Austin, Department of Biomedical Engineering, Austin, Texas, USA.
The University of Texas at Austin, Dell Medical School, Department of Internal Medicine, Austin, Texas, USA.
J Biomed Mater Res A. 2024 Apr;112(4):524-533. doi: 10.1002/jbm.a.37543. Epub 2023 Apr 8.
With new daily discoveries about the long-term impacts of COVID-19, there is a clear need to develop in vitro models that can be used to better understand the pathogenicity and impact of COVID-19. Here, we demonstrate the utility of developing a model of endothelial dysfunction that utilizes human induced pluripotent stem cell-derived endothelial progenitors encapsulated in collagen hydrogels to study the effects of COVID-19 on the endothelium. These cells form capillary-like vasculature within 1 week after encapsulation and treating these cell-laden hydrogels with SARS-CoV-2 spike protein resulted in a significant decrease in the number of vessel-forming cells as well as vessel network connectivity quantified by our computational pipeline. This vascular dysfunction is a unique phenomenon observed upon treatment with SARS-CoV-2 SP and is not seen upon treatment with other coronaviruses, indicating that these effects were specific to SARS-CoV-2. We show that this vascular dysfunction is caused by an increase in inflammatory cytokines, associated with the COVID-19 cytokine storm, released from SARS-CoV-2 spike protein treated endothelial cells. Following treatment with the corticosteroid dexamethasone, we were able to prevent SARS-CoV-2 spike protein-induced endothelial dysfunction. Our results highlight the importance of understanding the interactions between SARS-CoV-2 spike protein and the endothelium and show that even in the absence of immune cells, the proposed 3D in vitro model for angiogenesis can reproduce COVID-19-induced endothelial dysfunction seen in clinical settings. This model represents a significant step in creating physiologically relevant disease models to further study the impact of long COVID and potentially identify mitigating therapeutics.
随着每天都有关于新冠病毒长期影响的新发现，显然需要开发体外模型，以更好地了解新冠病毒的致病性和影响。在此，我们展示了开发一种内皮功能障碍模型的实用性，该模型利用封装在胶原蛋白水凝胶中的人诱导多能干细胞衍生的内皮祖细胞来研究新冠病毒对内皮的影响。这些细胞在封装后1周内形成毛细血管样脉管系统，用严重急性呼吸综合征冠状病毒2（SARS-CoV-2）刺突蛋白处理这些负载细胞的水凝胶，导致形成血管的细胞数量显著减少，以及通过我们的计算流程量化的血管网络连通性降低。这种血管功能障碍是在用SARS-CoV-2刺突蛋白处理时观察到的独特现象，在用其他冠状病毒处理时未观察到，表明这些影响是SARS-CoV-2特有的。我们表明，这种血管功能障碍是由炎症细胞因子增加引起的，这些细胞因子与新冠病毒细胞因子风暴相关，由经SARS-CoV-2刺突蛋白处理的内皮细胞释放。在用皮质类固醇地塞米松处理后，我们能够预防SARS-CoV-2刺突蛋白诱导的内皮功能障碍。我们的结果强调了理解SARS-CoV-2刺突蛋白与内皮之间相互作用的重要性，并表明即使在没有免疫细胞的情况下，所提出的用于血管生成的三维体外模型也可以重现临床环境中所见的新冠病毒诱导的内皮功能障碍。该模型代表了创建生理相关疾病模型以进一步研究长期新冠影响并潜在识别缓解疗法的重要一步。
