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