QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland 4006, Australia.
School of Biomedical Sciences, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.
Development. 2020 Nov 30;147(22):dev193417. doi: 10.1242/dev.193417.
The inability of the adult mammalian heart to regenerate represents a fundamental barrier in heart failure management. By contrast, the neonatal heart retains a transient regenerative capacity, but the underlying mechanisms for the developmental loss of cardiac regenerative capacity in mammals are not fully understood. Wnt/β-catenin signalling has been proposed as a key cardioregenerative pathway driving cardiomyocyte proliferation. Here, we show that Wnt/β-catenin signalling potentiates neonatal mouse cardiomyocyte proliferation and immature human pluripotent stem cell-derived cardiomyocyte (hPSC-CM) proliferation By contrast, Wnt/β-catenin signalling in adult mice is cardioprotective but fails to induce cardiomyocyte proliferation. Transcriptional profiling and chromatin immunoprecipitation sequencing of neonatal mouse and hPSC-CMs revealed a core Wnt/β-catenin-dependent transcriptional network governing cardiomyocyte proliferation. By contrast, β-catenin failed to re-engage this neonatal proliferative gene network in the adult heart despite partial transcriptional re-activation of a neonatal glycolytic gene programme. These findings suggest that β-catenin might be repurposed from regenerative to protective functions in the adult heart in a developmental process dependent on the metabolic status of cardiomyocytes.
成年哺乳动物心脏不能再生是心力衰竭治疗的一个基本障碍。相比之下，新生动物的心脏仍然具有短暂的再生能力，但哺乳动物中心脏再生能力发育丧失的潜在机制尚未完全阐明。Wnt/β-连环蛋白信号被认为是驱动心肌细胞增殖的关键心脏再生途径。在这里，我们表明 Wnt/β-连环蛋白信号增强了新生小鼠心肌细胞的增殖作用，并增强了未成熟的人类多能干细胞衍生的心肌细胞（hPSC-CM）的增殖作用。相比之下，成年小鼠中的 Wnt/β-连环蛋白信号具有心脏保护作用，但不能诱导心肌细胞增殖。对新生小鼠和 hPSC-CM 的转录谱分析和染色质免疫沉淀测序揭示了一个核心的 Wnt/β-连环蛋白依赖性转录网络，该网络控制着心肌细胞的增殖。相比之下，尽管新生糖酵解基因程序部分转录重新激活，但β-连环蛋白未能重新激活成年心脏中的这种新生增殖基因网络。这些发现表明，β-连环蛋白可能在发育过程中从再生功能重新定向为成年心脏的保护功能，这取决于心肌细胞的代谢状态。
