School of Biomedical Sciences, The University of Queensland, St Lucia 4072, QLD, Australia; Centre for Cardiac and Vascular Biology, The University of Queensland, St Lucia 4072, QLD, Australia; QIMR Berghofer Medical Research Institute, Brisbane 4006, QLD, Australia.
Charles Perkins Centre, School of Life and Environmental Science, The University of Sydney, Sydney 2006, NSW, Australia.
Cell Stem Cell. 2019 Jun 6;24(6):895-907.e6. doi: 10.1016/j.stem.2019.03.009. Epub 2019 Mar 28.
We have previously developed a high-throughput bioengineered human cardiac organoid (hCO) platform, which provides functional contractile tissue with biological properties similar to native heart tissue, including mature, cell-cycle-arrested cardiomyocytes. In this study, we perform functional screening of 105 small molecules with pro-regenerative potential. Our findings reveal surprising discordance between our hCO system and traditional 2D assays. In addition, functional analyses uncovered detrimental effects of many hit compounds. Two pro-proliferative small molecules without detrimental impacts on cardiac function were identified. High-throughput proteomics in hCO revealed synergistic activation of the mevalonate pathway and a cell-cycle network by the pro-proliferative compounds. Cell-cycle reentry in hCO and in vivo required the mevalonate pathway as inhibition of the mevalonate pathway with a statin attenuated pro-proliferative effects. This study highlights the utility of human cardiac organoids for pro-regenerative drug development, including identification of underlying biological mechanisms and minimization of adverse side effects.
我们之前开发了一种高通量的生物工程人心肌类器官（hCO）平台，该平台提供了具有类似于天然心脏组织的生物学特性的功能性收缩组织，包括成熟、细胞周期停滞的心肌细胞。在这项研究中，我们对 105 种具有再生潜力的小分子进行了功能筛选。我们的发现揭示了我们的 hCO 系统与传统的 2D 测定之间令人惊讶的不一致。此外，功能分析发现许多命中化合物具有有害影响。确定了两种对心脏功能没有不利影响的促增殖小分子。hCO 的高通量蛋白质组学揭示了促增殖化合物协同激活甲羟戊酸途径和细胞周期网络。hCO 和体内的细胞周期再进入需要甲羟戊酸途径，因为他汀类药物抑制甲羟戊酸途径会减弱促增殖作用。这项研究强调了人心肌类器官在促再生药物开发中的实用性，包括鉴定潜在的生物学机制和最小化不良反应。
