Arhontoulis Dimitrios C, Kerr Charles, Richards Dylan, Tjen Kelsey, Hyams Nathaniel, Jones Jefferey A, Deleon-Pennell Kristine, Menick Donald, Lindner Diana, Westermann Dirk, Mei Ying
Molecular and Cellular Biology and Pathobiology Program, Medical University of South Carolina, Charleston, SC, USA.
Bioengineering Department, Clemson University, Clemson, SC, USA.
bioRxiv. 2022 Feb 1:2022.01.31.478497. doi: 10.1101/2022.01.31.478497.
Acute cardiac injuries occur in 20-25% of hospitalized COVID-19 patients. Despite urgent needs, there is a lack of 3D organotypic models of COVID-19 hearts for mechanistic studies and drug testing. Herein, we demonstrate that human cardiac organoids (hCOs) are a viable platform to model the cardiac injuries caused by COVID-19 hyperinflammation. As IL-1βis an upstream cytokine and a core COVID-19 signature cytokine, it was used to stimulate hCOs to induce the release of a milieu of proinflammatory cytokines that mirror the profile of COVID-19 cytokine storm. The IL-1 β treated hCOs recapitulated transcriptomic, structural, and functional signatures of COVID-19 hearts. The comparison of IL-1β treated hCOs with cardiac tissue from COVID-19 autopsies illustrated the critical roles of hyper-inflammation in COVID-19 cardiac insults and indicated the cardioprotective effects of endothelium. The IL-1β treated hCOs also provide a viable model to assess the efficacy and potential side effects of immunomodulatory drugs, as well as the reversibility of COVID-19 cardiac injuries at baseline and simulated exercise conditions.
20%-25%的新冠病毒病住院患者会发生急性心脏损伤。尽管存在迫切需求,但缺乏用于机制研究和药物测试的新冠病毒病心脏的三维器官型模型。在此,我们证明人心脏类器官(hCOs)是模拟新冠病毒病过度炎症引起的心脏损伤的可行平台。由于白细胞介素-1β(IL-1β)是一种上游细胞因子且是新冠病毒病的核心标志性细胞因子,因此用它来刺激hCOs,以诱导释放一系列促炎细胞因子,这些细胞因子反映了新冠病毒病细胞因子风暴的特征。经IL-1β处理的hCOs概括了新冠病毒病心脏的转录组、结构和功能特征。将经IL-1β处理的hCOs与新冠病毒病尸检的心脏组织进行比较,阐明了过度炎症在新冠病毒病心脏损伤中的关键作用,并表明了内皮的心脏保护作用。经IL-1β处理的hCOs还提供了一个可行的模型,用于评估免疫调节药物的疗效和潜在副作用,以及在基线和模拟运动条件下新冠病毒病心脏损伤的可逆性。