Gladstone Institute of Cardiovascular Disease and Roddenberry Stem Cell Center, San Francisco, CA 94158, USA; Institute of Cardiovascular Sciences, University of Manchester, Manchester M13 9PT, UK; Faculty of Pharmacy, Zagazig University, Al Sharqia Governorate, Egypt; Tenaya Therapeutics, South San Francisco, CA 94080, USA.
Gladstone Institute of Cardiovascular Disease and Roddenberry Stem Cell Center, San Francisco, CA 94158, USA.
Cell. 2018 Mar 22;173(1):104-116.e12. doi: 10.1016/j.cell.2018.02.014. Epub 2018 Mar 1.
Human diseases are often caused by loss of somatic cells that are incapable of re-entering the cell cycle for regenerative repair. Here, we report a combination of cell-cycle regulators that induce stable cytokinesis in adult post-mitotic cells. We screened cell-cycle regulators expressed in proliferating fetal cardiomyocytes and found that overexpression of cyclin-dependent kinase 1 (CDK1), CDK4, cyclin B1, and cyclin D1 efficiently induced cell division in post-mitotic mouse, rat, and human cardiomyocytes. Overexpression of the cell-cycle regulators was self-limiting through proteasome-mediated degradation of the protein products. In vivo lineage tracing revealed that 15%-20% of adult cardiomyocytes expressing the four factors underwent stable cell division, with significant improvement in cardiac function after acute or subacute myocardial infarction. Chemical inhibition of Tgf-β and Wee1 made CDK1 and cyclin B dispensable. These findings reveal a discrete combination of genes that can efficiently unlock the proliferative potential in cells that have terminally exited the cell cycle.
人类疾病通常是由无法重新进入细胞周期进行再生修复的体细胞丧失引起的。在这里，我们报告了一种细胞周期调节剂的组合，它可以诱导成年有丝分裂后细胞的稳定胞质分裂。我们筛选了在增殖的胎儿心肌细胞中表达的细胞周期调节剂，发现细胞周期依赖性激酶 1 (CDK1)、CDK4、细胞周期蛋白 B1 和细胞周期蛋白 D1 的过表达可有效地诱导有丝分裂后小鼠、大鼠和人心肌细胞的细胞分裂。细胞周期调节剂的过表达通过蛋白酶体介导的蛋白产物降解而自我限制。体内谱系追踪显示，表达这四种因子的 15%-20%的成年心肌细胞经历了稳定的细胞分裂，急性或亚急性心肌梗死后心功能显著改善。Tgf-β 和 Wee1 的化学抑制使 CDK1 和细胞周期蛋白 B 变得可有可无。这些发现揭示了一种离散的基因组合，可以有效地释放已经退出细胞周期的细胞的增殖潜力。
