Fosl1 is vital to heart regeneration upon apex resection in adult Xenopus tropicalis.
Fosl1 is vital to heart regeneration upon apex resection in adult Xenopus tropicalis.
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Fosl1 对成年热带爪蟾心尖切除后的心脏再生至关重要
DOI：
10.1038/s41536-021-00146-y
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发表时间：
2021-06-29
影响因子：
7.2
通讯作者：
Qi XF
中科院分区：
文献类型：
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作者：
Wu HY;Zhou YM;Liao ZQ;Zhong JW;Liu YB;Zhao H;Liang CQ;Huang RJ;Park KS;Feng SS;Zheng L;Cai DQ;Qi XF
由于成人心脏丧失再生能力，心血管疾病是世界上导致死亡的主要原因。青蛙具有再生多种器官的非凡能力，包括脊髓、尾巴和肢体，但对心脏损伤的反应及其潜在的分子机制仍不清楚。在这里，我们证明心肌细胞增殖在心脏尖切除后极大地促进了成年热带凤梨的心脏再生。通过RNA-seq和qPCR，我们发现fos样抗原1 （Fosl1）的表达在心脏损伤早期显著上调。为了研究Fosl1在心脏再生中的功能，在体外和体内调节其表达。过表达热带扁扁杆菌Fosl1可显著促进心肌细胞系H9c2的增殖。一致地，内源性Fosl1敲低抑制从新生小鼠分离的H9c2细胞和原代心肌细胞的增殖。采用心肌细胞特异性显性阴性方法，我们发现阻断Fosl1功能会导致热带水仙心脏再生过程中心肌细胞增殖缺陷。我们进一步发现，敲低Fosl1可以抑制新生小鼠的心脏再生能力，而过表达Fosl1可以改善成年小鼠心肌梗死后的心脏功能。共免疫沉淀、荧光素酶报告基因和ChIP分析显示，Fosl1与JunB相互作用，促进心脏再生过程中Cyclin-T1 （Ccnt1）的表达。总之，我们证明了Fosl1在脊椎动物的心肌细胞增殖和心脏再生中发挥重要作用，至少部分是通过与JunB的相互作用，从而促进包括Ccnt1在内的细胞周期调节因子的表达。
Cardiovascular disease is the leading cause of death in the world due to losing regenerative capacity in the adult heart. Frogs possess remarkable capacities to regenerate multiple organs, including spinal cord, tail, and limb, but the response to heart injury and the underlying molecular mechanism remains largely unclear. Here we demonstrated that cardiomyocyte proliferation greatly contributes to heart regeneration in adult X. tropicalis upon apex resection. Using RNA-seq and qPCR, we found that the expression of Fos-like antigen 1 (Fosl1) was dramatically upregulated in early stage of heart injury. To study Fosl1 function in heart regeneration, its expression was modulated in vitro and in vivo. Overexpression of X. tropicalis Fosl1 significantly promoted the proliferation of cardiomyocyte cell line H9c2. Consistently, endogenous Fosl1 knockdown suppressed the proliferation of H9c2 cells and primary cardiomyocytes isolated from neonatal mice. Taking use of a cardiomyocyte-specific dominant-negative approach, we show that blocking Fosl1 function leads to defects in cardiomyocyte proliferation during X. tropicalis heart regeneration. We further show that knockdown of Fosl1 can suppress the capacity of heart regeneration in neonatal mice, but overexpression of Fosl1 can improve the cardiac function in adult mouse upon myocardium infarction. Co-immunoprecipitation, luciferase reporter, and ChIP analysis reveal that Fosl1 interacts with JunB and promotes the expression of Cyclin-T1 (Ccnt1) during heart regeneration. In conclusion, we demonstrated that Fosl1 plays an essential role in cardiomyocyte proliferation and heart regeneration in vertebrates, at least in part, through interaction with JunB, thereby promoting expression of cell cycle regulators including Ccnt1.
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