Distinct features of the regenerating heart uncovered through comparative single-cell profiling.
Distinct features of the regenerating heart uncovered through comparative single-cell profiling.
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通过比较单细胞分析揭示了再生心脏的独特特征。
DOI：
10.1101/2023.07.04.547574
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Gagnon,JamesA
中科院分区：
文献类型：
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作者：
Carey,ClaytonM;Hollins,HaileyL;Schmid,AlexisV;Gagnon,JamesA
成年人对心脏损伤的反应是形成永久性的疤痕，而其他脊椎动物则能够实现强大而完整的心脏再生。尽管在描述鱼类和两栖动物心脏再生机制方面取得了进展，但哺乳动物和再生脊椎动物之间巨大的进化鸿沟使破译哪些细胞和分子特征真正能够实现再生变得复杂。为了更好地定义这些特征，我们比较了斑马鱼和青鳉的心脏损伤反应，这两种鱼类具有相似的心脏解剖结构和共同的硬骨鱼祖先，但再生能力不同。我们使用单细胞转录谱来创建两个物种中所有主要心脏细胞类型的损伤反应的时间分辨比较细胞图谱。通过这种方法，我们确定了几个关键特征，区分非再生青鳉心脏的心脏损伤反应。通过比较对损伤的免疫反应，我们发现青鳉白细胞中细胞募集的改变和独特的促炎基因程序，以及在斑马鱼中观察到的损伤诱导的干扰素反应的缺乏。此外，我们发现青鳉内皮细胞和心外膜细胞缺乏促再生信号，包括nrg1和视黄酸。最后，我们确定了青鳉心肌结构的改变，它们缺乏原始层心肌细胞，并且未能采用再生脊椎动物共有的心脏保护基因程序。我们的研究结果揭示了斑马鱼和青鳉几乎所有主要心脏细胞类型的损伤反应的显着变化，表明进化分歧如何影响这些看似相似的脊椎动物中支撑再生潜力的隐藏细胞特征。
Adult humans respond to heart injury by forming a permanent scar, yet other vertebrates are capable of robust and complete cardiac regeneration. Despite progress towards characterizing the mechanisms of cardiac regeneration in fish and amphibians, the large evolutionary gulf between mammals and regenerating vertebrates complicates deciphering which cellular and molecular features truly enable regeneration. To better define these features, we compared cardiac injury responses in zebrafish and medaka, two fish species that share similar heart anatomy and common teleost ancestry but differ in regenerative capability. We used single-cell transcriptional profiling to create a time-resolved comparative cell atlas of injury responses in all major cardiac cell types across both species. With this approach, we identified several key features that distinguish cardiac injury response in the non-regenerating medaka heart. By comparing immune responses to injury, we found altered cell recruitment and a distinct pro-inflammatory gene program in medaka leukocytes, and an absence of the injury-induced interferon response seen in zebrafish. In addition, we found a lack of pro-regenerative signals, including nrg1 and retinoic acid, from medaka endothelial and epicardial cells. Finally, we identified alterations in the myocardial structure in medaka, where they lack primordial layer cardiomyocytes and fail to employ a cardioprotective gene program shared by regenerating vertebrates. Our findings reveal notable variation in injury response across nearly all major cardiac cell types in zebrafish and medaka, demonstrating how evolutionary divergence influences the hidden cellular features underpinning regenerative potential in these seemingly similar vertebrates.