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：
10464114
负责人：
Dimitrios Chrisovalantou Arhontoulis
金额：
$ 4.9万
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/10464114
关键词：
3-Dimensional Actinin Acute Address Adipose tissue Adrenergic Agents Animals Autopsy Biological Models Blood Circulation 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 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 Immunomodulators 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 combat cytokine cytokine release syndrome drug development drug testing experience heart function immune activation in vitro Model in vivo induced pluripotent stem cell derived cardiomyocytes innovation insight long term consequences of COVID-19 monocyte mortality response stem cells 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已感染了35,286,935人，死亡率为 1.73％。一种常见的COVID-19诱导并发症是心脏受损所表现出的急性心脏损伤功能。这些损伤与预后不良和COVID-19患者的死亡率增加有关。尽管急性心脏损伤是导致共同死亡率的主要因素，但根本原因尚未阐明。在多种因素（例如，直接病毒感染）可以导致COVID-19引起的心肌病，最近的临床数据表明细胞因子风暴是主要因素。 2019冠状病毒病感染启动免疫系统的超催化性激活，这导致炎症的释放细胞因子（例如IL-1E，IL-2，IL-6，IL-10，TNFD，G-CSF和MIP1D）进入循环，导致器官毒性这样作为血管不稳定性和不良心脏事件。尽管Covid-19 Cytokine风暴在急性中起关键作用心脏损伤，目前缺乏动物和体外模型限制了机械理解和药物开发。此外，虽然最近的临床数据表明Covid-19患有急性心脏的幸存者受伤可能会遭受长期心脏异常，结果研究可能需要数年才能完成这种冠状病毒的新颖性。这突出了开发有效模型的未满足需要，该模型可以预测长期康复期COVID-19患者的术语心脏结局，以提供临床监测和治疗干预措施。我们的类器官提供了一个强大的平台来解决这一问题。器官是由HIPSC衍生的心肌细胞，人心脏成纤维细胞，人内皮细胞和血管组成支持细胞。该提案的目的是为COVID-19的细胞因子风暴开发体外模型通过利用细胞的先天炎症特性（例如，成纤维细胞，内皮细胞）来急性心脏损伤在器官中，由于这些细胞已被证明在下面产生各种促炎细胞因子刺激。 IL-1E是响应病毒感染的最早从单核细胞释放的细胞因子之一，已知诱导IL-6生产，这是Cytokine风暴中的中心参与者。该提议的核心假设是 IL-1E将在器官中诱导细胞因子风暴，并概括COVID-19诱导的急性心脏损伤。该建议具有创新性，因为我们将利用病毒感染引起的上游细胞因子刺激（IL-1E）发起内源性炎症反应以模拟类器官中的细胞因子风暴。因此，我们将追求这两个目的：1）使用IL-1E处理的心脏器官进行模拟COVID-19的细胞因子风暴诱导心脏损伤，确定潜在机制并测试免疫调节药物的作用，2）使用人体心脏器官评估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COVID-的基本机制 19细胞因子风暴诱导心脏损伤，证明了其在药物测试中的有效性，并提供了有关 COVID-19感染的长期心脏影响指导临床监测和治疗干预措施。