昆士兰大学James E. Hudson课题组在研究中取得进展。他们发现了药物筛选在人类类心脏器官鉴定促增殖化合物的甲羟戊酸途径。 2019年3月28日，知名学术期刊《细胞—干细胞》发表了这一成果。

研究小组之前已经开发出一个高通量的生物工程人类心脏组织(hCO)平台，它提供了与天然心脏组织类似的功能收缩组织，包括成熟的、细胞周期阻滞的心肌细胞。在这项研究中，该团队对105个具有再生潜能的小分子进行了功能筛选。他们揭示了hCO系统和传统二维分析之间的不一致性。此外，功能分析揭示了许多化合物的有害影响，确定了两种不影响心脏功能的促增殖小分子。hCO高通量蛋白质组学显示，促增殖化合物协同激活甲羟戊酸途径和细胞周期网络。细胞周期再进入hCO和体内需要甲羟戊酸途径作为抑制甲羟戊酸途径与他汀类药物减弱促增殖作用。

该研究强调了人类心脏类器官在促进再生药物开发中的作用，包括识别潜在的生物学机制和将副作用最小化。

附：英文原文

Title: Drug Screening in Human PSC-Cardiac Organoids Identifies Pro-proliferative Compounds Acting via the Mevalonate Pathway

Author: Richard J. Mills, Benjamin L. Parker, Gregory A. Quaife-Ryan, David E. James, Enzo R. Porrello, James E. Hudson

Issue&Volume:Jun 06, 2019 Volume 24Issue 6

Abstract: 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.

DOI: https://doi.org/10.1016/j.stem.2019.03.009

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(19)30108-0