p53 isoform Delta 113p53 promotes zebrafish heart regeneration by maintaining redox homeostasis
p53 isoform Delta 113p53 promotes zebrafish heart regeneration by maintaining redox homeostasis
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p53 异构体 Delta 113p53 通过维持氧化还原稳态促进斑马鱼心脏再生
DOI：
10.1038/s41419-020-02781-7
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发表时间：
2020
影响因子：
9
通讯作者：
Chen Jun
中科院分区：
文献类型：
--
作者：
Ye Shengfan;Zhao Ting;Zhang Wei;Tang Zimu;Gao Ce;Ma Zhipeng;Xiong Jing-Wei;Peng Jinrong;Tan Wei-Qiang;Chen Jun
新生小鼠和成年斑马鱼可以通过预先存在的心肌细胞的增殖来完全再生它们的心脏。先前的研究表明，p53信号在新生小鼠心脏再生过程中被激活，伤口附近产生的过氧化氢（H2O2）可作为促进斑马鱼心脏再生的新信号。我们最近证明，p53亚型Δ133p53的表达在低水平活性氧（ROS）刺激下高度诱导，并且Δ133p53与全长p53协调，通过增强抗氧化基因的表达来促进细胞存活。然而，p53 信号在心脏再生中的功能仍然未知。在这里，我们发现Δ113p53的表达在斑马鱼心脏切除部位的心肌细胞中以全长p53和ROS信号依赖的方式被激活。细胞谱系追踪显示Δ113p53阳性心肌细胞经历细胞增殖并有助于心肌再生。更重要的是，Δ113p53M/M突变斑马鱼的心脏再生受到损害。 Δ113p53的耗竭显着降低了心肌细胞的增殖频率，但对gata4阳性细胞的激活、其向伤口部位边缘的迁移或凋亡活性几乎没有影响。完整心脏的实时成像显示，Δ113p53M/M突变体中切除部位的H2O2诱导显着高于野生型斑马鱼，这可能是Δ113p53M/M突变体中抗氧化基因诱导减少的结果。我们的研究结果表明，切除部位心肌细胞中Δ113p53的诱导可通过增加抗氧化基因的表达来维持氧化还原稳态，从而促进心脏再生。
Neonatal mice and adult zebrafish can fully regenerate their hearts through proliferation of pre-existing cardiomyocytes. Previous studies have revealed that p53 signalling is activated during cardiac regeneration in neonatal mice and that hydrogen peroxide (H2O2) generated near the wound site acts as a novel signal to promote zebrafish heart regeneration. We recently demonstrated that the expression of the p53 isoformΔ133p53is highly induced upon stimulation by low-level reactive oxygen species (ROS) and that Δ133p53 coordinates with full-length p53 to promote cell survival by enhancing the expression of antioxidant genes. However, the function of p53 signalling in heart regeneration remains uncharacterised. Here, we found that the expression ofΔ113p53is activated in cardiomyocytes at the resection site in the zebrafish heart in a full-length p53- and ROS signalling-dependent manner. Cell lineage tracing showed thatΔ113p53-positive cardiomyocytes undergo cell proliferation and contribute to myocardial regeneration. More importantly, heart regeneration is impaired inΔ113p53M/Mmutant zebrafish. Depletion ofΔ113p53significantly decreases the proliferation frequency of cardiomyocytes but has little effect on the activation ofgata4-positive cells, their migration to the edge of the wound site, or apoptotic activity. Live imaging of intact hearts showed that induction of H2O2at the resection site is significantly higher inΔ113p53M/Mmutants than in wild-type zebrafish, which may be the result of reduced induction of antioxidant genes inΔ113p53M/Mmutants. Our findings demonstrate that induction ofΔ113p53in cardiomyocytes at the resection site functions to promote heart regeneration by increasing the expression of antioxidant genes to maintain redox homeostasis.