Complement Receptor C5aR1 Plays an Evolutionarily Conserved Role in Successful Cardiac Regeneration.
Complement Receptor C5aR1 Plays an Evolutionarily Conserved Role in Successful Cardiac Regeneration.
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DOI：
10.1161/circulationaha.117.030801
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发表时间：
2018-05-15
期刊：
影响因子：
37.8
通讯作者：
Lee RT
中科院分区：
文献类型：
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作者：
Natarajan N;Abbas Y;Bryant DM;Gonzalez-Rosa JM;Sharpe M;Uygur A;Cocco-Delgado LH;Ho NN;Gerard NP;Gerard CJ;MacRae CA;Burns CE;Burns CG;Whited JL;Lee RT
在成功心脏再生的动物模型中定义保守的分子途径可以深入了解为什么成年哺乳动物在损伤后心脏再生不足。从模式生物中深入了解早期心脏再生的转录组学景观，将有助于阐明成功心脏再生中进化保守的途径。在这里，我们描述了一个跨物种的转录组筛选在三个模式生物心脏再生-蝾螈，新生小鼠和斑马鱼。在这些模型生物体中进行心尖切除以去除约10 - 20%的心室质量。对在切除后12、24和48小时的三个时间点收获的心脏进行RNA-seq分析。假手术用作内部对照。发现与炎症过程相关的基因以保守的方式上调。补体受体（由补体成分激活，先天免疫系统的一部分）被发现在所有三个物种中高度上调。这种方法揭示了斑马鱼、蝾螈和小鼠再生心脏中补体5a受体1（C5 aR 1）的基因表达诱导。抑制C5 aR 1显着减弱心肌细胞增殖反应的心脏损伤在所有三个物种。此外，左心室心尖切除术后，C5 aR 1基因缺失小鼠的心肌细胞增殖反应被取消。这些数据表明，C5 aR 1的激活介导了一种进化上保守的反应，促进心脏损伤后的心肌细胞增殖，并将补体途径激活确定为成功心脏再生的共同途径。
Defining conserved molecular pathways in animal models of successful cardiac regeneration could yield insight into why adult mammals have inadequate cardiac regeneration after injury. Insight into the transcriptomic landscape of early cardiac regeneration from model organisms will shed light on evolutionarily conserved pathways in successful cardiac regeneration. Here we describe a cross-species transcriptomic screen in three model organisms for cardiac regeneration –axolotl, neonatal mice and zebrafish. Apical resection to remove ~10 – 20% of ventricular mass was carried out in these model organisms. RNA-seq analysis was performed on the hearts harvested at three time points – 12, 24 and 48 hours post-resection. Sham surgery was used as internal control. Genes associated with inflammatory processes were found to be upregulated in a conserved manner. Complement receptors (activated by complement components, part of the innate immune system) were found to be highly upregulated in all three species. This approach revealed induction of gene expression for Complement 5a receptor1 (C5aR1) in the regenerating hearts of zebrafish, axolotls and mice. Inhibition of C5aR1 significantly attenuated the cardiomyocyte proliferative response to heart injury in all three species. Furthermore, following left ventricular apical resection, the cardiomyocyte proliferative response was abolished in mice with genetic deletion of C5aR1. These data reveal that activation of C5aR1 mediates an evolutionarily conserved response that promotes cardiomyocyte proliferation following cardiac injury and identify complement pathway activation as a common pathway of successful heart regeneration.