Carey Clayton M, Hollins Hailey L, Schmid Alexis V, Gagnon James A
School of Biological Sciences, University of Utah, Salt Lake City, UT, 84112, USA.
Henry Eyring Center for Cell & Genome Science, University of Utah, Salt Lake City, UT 84112, USA.
bioRxiv. 2023 Jul 12:2023.07.04.547574. doi: 10.1101/2023.07.04.547574.
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 embryonic-like 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.
成年人类通过形成永久性疤痕来应对心脏损伤，而其他脊椎动物则能够进行强大且完全的心脏再生。尽管在表征鱼类和两栖动物心脏再生机制方面取得了进展，但哺乳动物与能够进行心脏再生的脊椎动物之间巨大的进化差异，使得解读哪些细胞和分子特征真正促成再生变得复杂。为了更好地定义这些特征，我们比较了斑马鱼和青鳉这两种鱼类的心脏损伤反应，它们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分析，创建了这两个物种所有主要心脏细胞类型损伤反应的时间分辨比较细胞图谱。通过这种方法，我们确定了几个区分青鳉这种非再生心脏中心脏损伤反应的关键特征。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发生改变且有独特的促炎基因程序，并且没有斑马鱼中出现的损伤诱导的干扰素反应。此外，我们发现青鳉内皮细胞和心外膜细胞缺乏包括神经调节蛋白1和视黄酸在内的促再生信号。最后，我们确定了青鳉心肌结构的改变，它们缺乏类似胚胎的原始层心肌细胞，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在损伤反应上的显著差异，证明了进化差异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。
