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

使用人类心脏类器官模拟 COVID-19 细胞因子风暴诱发的心脏损伤

基本信息

批准号：
10733416
负责人：
Dimitrios Chrisovalantou Arhontoulis
金额：
$ 4.99万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10733416
关键词：
3-Dimensional Actinin Acute Address Adrenergic Agents Animals Autopsy Biological Models Blood Vessels COVID-19 COVID-19 complications COVID-19 cytokine storm COVID-19 impact COVID-19 mortality COVID-19 patient COVID-19 survivors CSF3 gene Calcium Signaling Cardiac Cardiac Myocytes Cardiomyopathies Cell Communication Cells Cessation of life Chronic Circulation Clinical Clinical Data Complication Coronavirus Data Dexamethasone Diffusion Disease model Dose EFRAC Endothelial Cells Event Fibroblasts Genetic Transcription Goals Heart Heart Abnormalities Heart Injuries Heart failure Human Hypoxia Immune system Impairment In Situ Nick-End Labeling Inflammation Inflammatory Inflammatory Response Injury Interleukin-10 Interleukin-2 Interleukin-6 Long-Term Effects Modeling Monitor Myocardial Infarction Myocardium Norepinephrine Organ Organoids Outcome Outcome Study Oxygen PECAM1 gene Persons Pharmacotherapy Phase Prevalence Production Prognosis Property Recovery Research Role SARS-CoV-2 infection Sampling Stimulus Stromal Cells Structure Supporting Cell System Testing Therapeutic Intervention Toxic effect Umbilical vein VWF gene Vimentin Virus Diseases adipose derived stem cell combat cytokine cytokine release syndrome drug development drug testing experience heart function immune activation immune modulating agents in vitro Model in vivo induced pluripotent stem cell derived cardiomyocytes innovation insight long term consequences of COVID-19 monocyte mortality response transcriptome transcriptome sequencing

项目摘要

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.

摘要：截至 2021 年 8 月 4 日，COVID-19 已在美国感染 35,286,935 人，死亡率为 1.73%。 COVID-19 引起的一种常见并发症是急性心脏损伤，表现为心脏受损功能。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导致 COVID-19 死亡的主要原因，但其根本原因尚未明确阐明了。多种因素（例如直接病毒感染）可能导致 COVID-19 诱发心肌病，最近的临床数据表明细胞因子风暴是一个主要因素。 2019冠状病毒病感染启动免疫系统的超生理激活，从而导致炎症释放细胞因子（例如 IL-1E、IL-2、IL-6、IL-10、TNFD、G-CSF 和 MIP1D）进入循环，导致器官毒性，例如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机制的理解和药物开发。此外，虽然最近的临床数据表明患有急性心脏病的 COVID-19 幸存者受伤可能会经历长期的心脏异常，由于以下原因，结果研究可能需要数年时间才能完成这种冠状病毒的新颖性。这凸显了开发一种可以预测长期影响的有效模型的需求尚未得到满足。恢复期 COVID-19 患者的足月心脏结局，为临床监测和治疗提供指导治疗干预。我们的类器官提供了一个强大的平台来解决这个问题。类器官是由 hiPSC 来源的心肌细胞、人心脏成纤维细胞、人内皮细胞和血管组成支持细胞。该提案的目标是开发一种用于 COVID-19 诱导的细胞因子风暴的体外模型利用细胞（例如成纤维细胞、内皮细胞）的先天炎症特性来治疗急性心脏损伤在类器官中，因为这些细胞已被证明可以产生各种促炎细胞因子刺激。 IL-1E 是单核细胞响应病毒感染而首先释放的细胞因子之一，已知诱导IL-6的产生，IL-6是细胞因子风暴的核心角色。该提案的中心假设是 IL-1E 将在类器官中诱导细胞因子风暴，并重现 COVID-19 引起的急性心脏损伤。该提案的创新之处在于我们将利用病毒感染诱导的上游细胞因子刺激物（IL-1E）启动内源性炎症反应，模拟类器官中的细胞因子风暴。据此，我们将追求两个目标：1) 使用 IL-1E 处理的心脏类器官来模拟 COVID-19 诱导的细胞因子风暴心脏损伤，确定潜在机制，并测试免疫调节药物的效果，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。这拟议的研究将建立一个体外模型系统，以阐明新冠病毒的基本机制 19 细胞因子风暴诱发的心脏损伤，证明其对药物测试的有效性，并提供有关 COVID-19 感染的长期心脏影响，以指导临床监测和治疗干预。