Complement Activation and Initiation of Heart Regeneration

成人心脏不能用足够的新的心肌细胞重新填充心肌 损伤，这种有限的再生能力可能会导致收缩性心力衰竭。相比之下，来自 不同的类群，包括成年火蜥蜴和斑马鱼，都有非凡的能力来完成 心脏损伤后的心肌再生。我们与其他多个实验室合作， 进行无偏见的基因组筛选以确定心脏期间差异表达的基因 三个具有增强再生能力的模型系统的再生：斑马鱼，Axolotl (墨西哥鳗鱼)和新生的小鼠。我们鉴定出了该基因 补体5a受体C5aR1将在接下来的48小时内在再生心脏中诱导 在所有这些物种中都受到了伤害，并进一步表明这种表达的增加主要局限于 心肌细胞和血管内皮细胞。C5aR1是一种G蛋白偶联受体，是重要的受体之一 被补体级联的C5a多肽激活。补体途径是一条古老的、高度 保守的免疫反应系统，能激活炎症，促进外源和外源的清除 损坏的材料。当补体系统被激活时，一系列顺序的切割和 下游的激活步骤发生，导致扩增，并最终激活一个共同的途径 多个G蛋白偶联受体，包括C5aR1，这是该项目的重点。在这里我们展示了初步的 数据显示，心脏损伤后抑制C5aR1受体会损害心肌细胞 Axolotl和新生小鼠对根尖切除的周期反应，提示补体 在成功的心脏再生中，激活和信号传递可能代表了一条进化上保守的途径。 正如本提案中所描述的，该项目旨在揭示激活的补体如何 途径促进心脏再生。我们的中心理论是补体途径发挥着 通过协调分子信号在心脏再生反应中的进化保守作用 急性损伤和心肌细胞增殖，这是心脏再生的关键组成部分。该项目有三个 假说-驱动机制的目标，重点是新生小鼠作为哺乳动物的心脏再生系统。 了解心脏成功再生的早期事件可能会让我们理性地干预 促进严重损伤的成人心脏的再生，例如在相当大的心脏损伤后的头几天 脑梗塞。

The adult human heart fails to repopulate the myocardium with sufficient new cardiomyocytes following injury, and this limited capacity for regeneration can lead to systolic heart failure. In contrast, organisms from diverse taxa including adult salamanders and zebrafish have remarkable abilities to achieve complete regeneration of the myocardium following heart injury. We collaborated with multiple other laboratories to perform an unbiased genomic screen to identify genes that are differentially expressed during heart regeneration in three well-described model systems with enhanced regenerative capabilities: zebrafish, axolotl (Ambystoma mexicanum, or the Mexican salamander) and neonatal mice. We identified the gene for the complement 5a receptor, C5aR1, to be induced in the regenerating heart within the first 48 hours following injury in all of these species, and further showed that this increase in expression is primarily localized to cardiomyocytes and endothelial cells. C5aR1 is a G-protein coupled receptor that is one of the key receptors activated by the C5a peptide of the complement cascade. The complement pathway is an ancient and highly conserved immune response system that can activate inflammation and promote clearance of foreign and damaged materials. When the complement system is activated, a series of sequential cleavage and downstream activation steps occur, leading to amplification and eventually a common pathway activation of multiple G-protein coupled receptors, including C5aR1, the focus of this project. Here we show preliminary data demonstrating that inhibition of the C5aR1 receptor following cardiac injury impairs the cardiomyocyte cell cycle response to apical resection in axolotl as well as in the neonatal mouse, suggesting that complement activation and signaling could represent an evolutionarily conserved pathway in successful heart regeneration. As described in this proposal, this project aims to reveal the mechanism of how the activated complement pathway promotes heart regeneration. Our central theory is that the complement pathway plays an evolutionarily-conserved role in the heart regenerative response by orchestrating molecular signaling between acute injury and cardiomyocyte proliferation, a crucial component of heart regeneration. The project has three hypothesis-drive mechanistic aims, focusing on neonatal mice as the mammalian heart regeneration system. Understanding the early events in successful heart regeneration may allow us to intervene rationally to promote regeneration in the acutely injured adult human heart, such as in the first days after a sizable infarction.