期刊
CELL STEM CELL
卷 24, 期 6, 页码 895-+出版社
CELL PRESS
DOI: 10.1016/j.stem.2019.03.009
关键词
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资金
- National Health and Medical Research Council
- National Heart Foundation
- Stem Cells Australia
- Royal Children's Hospital Foundation
- University of Queensland
- QIMR Berghofer Medical Research Institute
- Victorian Government's Operational Infrastructure Support Program
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.
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