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

• 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
• 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

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，美国新冠肺炎感染人数为35,286,935人，死亡率为