Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA (N.N., Y.A., D.M.B., A.U., L.H.C.-D., N.N.H., J.L.W., R.T.L.).
Department of Orthopedic Surgery, Brigham & Women's Hospital, Cambridge, MA (D.M.B., J.L.W.).
Circulation. 2018 May 15;137(20):2152-2165. doi: 10.1161/CIRCULATIONAHA.117.030801. Epub 2018 Jan 18.
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 3 model organisms for cardiac regeneration: axolotl, neonatal mice, and zebrafish. Apical resection to remove ≈10% to 20% of ventricular mass was carried out in these model organisms. RNA-sequencing analysis was performed on the hearts harvested at 3 time points: 12, 24, and 48 hours after 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 3 species. This approach revealed induction of gene expression for complement 5a receptor 1 in the regenerating hearts of zebrafish, axolotls, and mice. Inhibition of complement 5a receptor 1 significantly attenuated the cardiomyocyte proliferative response to heart injury in all 3 species. Furthermore, after left ventricular apical resection, the cardiomyocyte proliferative response was diminished in mice with genetic deletion of complement 5a receptor 1.
These data reveal that activation of complement 5a receptor 1 mediates an evolutionarily conserved response that promotes cardiomyocyte proliferation after cardiac injury and identify complement pathway activation as a common pathway of successful heart regeneration.
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受伤后心脏再生不足。了解来自模式生物的早期心脏再生的转录组景观将揭示成功心脏再生中保守的途径。
在这里，我们描述了 3 种模型生物（蝾螈、新生小鼠和斑马鱼）的跨物种转录组筛选，用于心脏再生。在这些模型生物中进行心尖切除术，切除约 10%至 20%的心室质量。在切除后 12、24 和 48 小时收获心脏，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（被补体成分激活，是先天免疫系统的一部分）在所有 3 个物种中均高度上调。这种方法揭示了在斑马鱼、蝾螈和小鼠的再生心脏中，补体 5a 受体 1 的基因表达被诱导。补体 5a 受体 1 的抑制显著减弱了所有 3 个物种中心肌细胞对心脏损伤的增殖反应。此外，在心尖左心室切除后，补体 5a 受体 1 基因缺失的小鼠心肌细胞增殖反应减弱。
这些数据表明，补体 5a 受体 1 的激活介导了一种进化上保守的反应，促进了心脏损伤后的心肌细胞增殖，并确定了补体途径的激活是成功心脏再生的共同途径。
