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Regulation of Cell Cycle to Stimulate Adult Cardiomyocyte Proliferation and Cardiac Regeneration.
Cell ( IF 45.5 ) Pub Date : 2018-Mar-22 , DOI: 10.1016/j.cell.2018.02.014 Tamer M A Mohamed 1 , Yen-Sin Ang 2 , Ethan Radzinsky 2 , Ping Zhou 2 , Yu Huang 2 , Arye Elfenbein 2 , Amy Foley 2 , Sergey Magnitsky 3 , Deepak Srivastava 4
Cell ( IF 45.5 ) Pub Date : 2018-Mar-22 , DOI: 10.1016/j.cell.2018.02.014 Tamer M A Mohamed 1 , Yen-Sin Ang 2 , Ethan Radzinsky 2 , Ping Zhou 2 , Yu Huang 2 , Arye Elfenbein 2 , Amy Foley 2 , Sergey Magnitsky 3 , Deepak Srivastava 4
Affiliation
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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.
中文翻译：
调节细胞周期刺激成体心肌细胞增殖和心脏再生。
人类疾病通常是由于体细胞丧失而导致无法重新进入细胞周期进行再生修复。在这里，我们报告了细胞周期调节剂的组合，可在成年有丝分裂后细胞中诱导稳定的胞质分裂。我们筛选了增殖胎儿心肌细胞中表达的细胞周期调节因子，发现细胞周期蛋白依赖性激酶 1 (CDK1)、CDK4、细胞周期蛋白 B1 和细胞周期蛋白 D1 的过度表达可有效诱导有丝分裂后小鼠、大鼠和人心肌细胞的细胞分裂。细胞周期调节因子的过度表达通过蛋白酶体介导的蛋白质产物降解来自我限制。体内谱系追踪显示，表达四种因子的成体心肌细胞中有15%-20%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着改善。 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。这些发现揭示了基因的离散组合，可以有效地释放最终退出细胞周期的细胞的增殖潜力。
更新日期：2018-03-02
中文翻译：
调节细胞周期刺激成体心肌细胞增殖和心脏再生。
人类疾病通常是由于体细胞丧失而导致无法重新进入细胞周期进行再生修复。在这里，我们报告了细胞周期调节剂的组合，可在成年有丝分裂后细胞中诱导稳定的胞质分裂。我们筛选了增殖胎儿心肌细胞中表达的细胞周期调节因子，发现细胞周期蛋白依赖性激酶 1 (CDK1)、CDK4、细胞周期蛋白 B1 和细胞周期蛋白 D1 的过度表达可有效诱导有丝分裂后小鼠、大鼠和人心肌细胞的细胞分裂。细胞周期调节因子的过度表达通过蛋白酶体介导的蛋白质产物降解来自我限制。体内谱系追踪显示，表达四种因子的成体心肌细胞中有15%-20%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着改善。 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。这些发现揭示了基因的离散组合，可以有效地释放最终退出细胞周期的细胞的增殖潜力。
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