The Use of Human Cardiac Organoids to Model COVID-19 Cytokine Storm Induced Cardiac Injury

摘要：截至2021年8月4日，COVID-19已在美国感染了35，286，935人，死亡率为 百分之一点七三。一种常见的COVID-19引起的并发症是急性心脏损伤，表现为心脏功能受损， 功能这些损伤与COVID-19患者的预后不良和死亡率增加有关。 虽然急性心脏损伤是COVID-19死亡率的主要原因，但其根本原因尚未得到解决。 阐明。在多个因素（例如，直接病毒感染），可能导致COVID-19诱导 在心肌病中，最近的临床数据表明细胞因子风暴是主要贡献者。COVID-19感染 启动免疫系统的超生理激活，导致炎症释放 细胞因子（例如，IL-1 E、IL-2、IL-6、IL-10、TNFD、G-CSF和MIP 1D）进入循环，导致器官毒性，例如 血管不稳定和不良心脏事件尽管COVID-19细胞因子风暴在急性 心脏损伤，目前缺乏动物和体外模型，限制了对机制的理解， 药物开发此外，虽然最近的临床数据表明，患有急性心脏病的COVID-19幸存者 损伤可能会经历长期的心脏异常，结果研究可能需要数年才能完成， 这种冠状病毒的新奇。这突出了一个未满足的需要，即开发一个有效的模型，可以预测长期的- 恢复期COVID-19患者的长期心脏结局，为临床监测和 治疗干预。我们的类器官提供了一个强大的平台来解决这个问题。所述类器官是 由hiPSC衍生的心肌细胞、人心脏成纤维细胞、人内皮细胞和血管内皮细胞组成。 支持细胞。该提案的目标是开发COVID-19细胞因子风暴诱导的体外模型， 急性心脏损伤通过利用细胞的先天炎症特性（例如，成纤维细胞、内皮细胞） 在类器官中，由于这些细胞已被证明在炎症条件下产生各种促炎细胞因子， 刺激. IL-1 E是响应病毒感染从单核细胞释放的第一批细胞因子之一， 以诱导IL-6的产生，IL-6是细胞因子风暴中的中心角色。这一提议的核心假设是， IL-1 E将在类器官中诱导细胞因子风暴，并重现COVID-19诱导的急性心脏损伤。 这项提议是创新的，因为我们将利用病毒感染诱导的上游细胞因子刺激（IL-1 E） 以启动内源性炎症反应，从而模拟类器官中的细胞因子风暴。因此我们 将追求两个目标：1）使用IL-1 E处理的心脏类器官来模拟COVID-19细胞因子风暴诱导的 心脏损伤，确定潜在机制，并测试免疫调节药物的作用，以及2） 使用人类心脏类器官评估COVID-19细胞因子风暴的长期心脏并发症。的 拟议的研究将建立一个体外模型系统，以阐明COVID的基本机制， 19细胞因子风暴诱导的心脏损伤，证明其有效性的药物测试，并提供见解， COVID-19感染对心脏的长期影响，以指导临床监测和治疗干预。

Abstract: As of August 4, 2021, COVID-19 has infected 35,286,935 people in the US with a mortality rate of 1.73%. One common COVID-19 induced complication is acute cardiac injury manifested by impaired cardiac function. These injuries have been associated with poor prognosis and increased mortality for COVID-19 patients. While acute cardiac injury is a major contributor to COVID-19 mortality, the underlying causes have not been elucidated. Among multiple factors (e.g., direct viral infection) that can contribute to COVID-19 induced cardiomyopathies, recent clinical data indicates that cytokine storm is a major contributor. COVID-19 infection initiates supraphysiological activation of the immune system, which leads to the release of inflammatory cytokines (e.g., IL-1E, IL-2, IL-6, IL-10, TNFD, G-CSF and MIP1D) into circulation, resulting in organ toxicity such as vascular instability and adverse cardiac events. Despite the critical roles of COVID-19 cytokine storm in acute cardiac injury, the current lack of animal and in vitro models has limited the mechanistic understanding and drug development. Further, while recent clinical data suggests that COVID-19 survivors with acute cardiac injuries can experience long-term cardiac abnormalities, outcome studies may take years to complete due to the novelty of this coronavirus. This highlights an unmet need to develop an effective model that can predict long- term cardiac outcomes of convalescent COVID-19 patients to provide guidance for clinical monitoring and therapeutic interventions. Our organoids provide a powerful platform to address this. The organoids are composed of hiPSC derived cardiomyocytes, human cardiac fibroblasts, human endothelial cells, and vascular supporting cells. The goal of this proposal is to develop an in vitro model for COVID-19 cytokine storm induced acute cardiac injuries by leveraging the innate inflammatory properties of cells (e.g., fibroblasts, endothelial cells) in the organoids, as these cells have been shown to produce various proinflammatory cytokines under stimulation. IL-1E is one of the first cytokines released from monocytes in response to viral infection and is known to induce IL-6 production, the central player in cytokine storm. The central hypothesis of this proposal is that IL-1E will induce cytokine storm in the organoids and recapitulate the COVID-19 induced acute cardiac injuries. This proposal is innovative in that we will harness a viral infection induced upstream cytokine stimulus (IL-1E) to initiate an endogenous inflammatory response to simulate cytokine storm in the organoids. Accordingly, we will pursue the two aims: 1) Use IL-1E treated cardiac organoids to model COVID-19 cytokine storm induced cardiac injuries, determine the underlying mechanisms, and test the effects of immunomodulatory drugs, and 2) Use human cardiac organoids to assess the long-term cardiac complications of COVID-19 cytokine storm. The proposed research will establish an in vitro model system to elucidate the fundamental mechanisms of COVID- 19 cytokine storm induced cardiac injuries, demonstrate its validity for drug testing, and provide insights on the long-term cardiac effects of COVID-19 infection to guide clinical monitoring and therapeutic interventions.