Hubrecht Institute-KNAW and University Medical Center Utrecht, 3584CT Utrecht, The Netherlands.
Department of Cell and Chemical Biology, Leiden University Medical Centre, 2333ZC Leiden, The Netherlands.
Development. 2021 Oct 1;148(19). doi: 10.1242/dev.198937. Epub 2021 Oct 4.
Fibroblasts are activated to repair the heart following injury. Fibroblast activation in the mammalian heart leads to a permanent fibrotic scar that impairs cardiac function. In other organisms, such as zebrafish, cardiac injury is followed by transient fibrosis and scar-free regeneration. The mechanisms that drive scarring versus scar-free regeneration are not well understood. Here, we show that the homeobox-containing transcription factor Prrx1b is required for scar-free regeneration of the zebrafish heart as the loss of Prrx1b results in excessive fibrosis and impaired cardiomyocyte proliferation. Through lineage tracing and single-cell RNA sequencing, we find that Prrx1b is activated in epicardial-derived cells where it restricts TGFβ ligand expression and collagen production. Furthermore, through combined in vitro experiments in human fetal epicardial-derived cells and in vivo rescue experiments in zebrafish, we conclude that Prrx1 stimulates Nrg1 expression and promotes cardiomyocyte proliferation. Collectively, these results indicate that Prrx1 is a key transcription factor that balances fibrosis and regeneration in the injured zebrafish heart. This article has an associated 'The people behind the papers' interview.
成纤维细胞在受伤后被激活以修复心脏。哺乳动物心脏中的成纤维细胞活化导致永久性纤维化瘢痕，从而损害心脏功能。在其他生物体中，如斑马鱼，心脏损伤后会出现短暂的纤维化和无瘢痕再生。导致瘢痕形成和无瘢痕再生的机制尚不清楚。在这里，我们表明，含有同源盒的转录因子 Prrx1b 是斑马鱼心脏无瘢痕再生所必需的，因为 Prrx1b 的缺失会导致过度纤维化和心肌细胞增殖受损。通过谱系追踪和单细胞 RNA 测序，我们发现 Prrx1b 在心脏外膜衍生细胞中被激活，在那里它限制 TGFβ 配体的表达和胶原蛋白的产生。此外，通过在人胎儿心脏外膜衍生细胞中的体外实验和在斑马鱼中的体内挽救实验，我们得出结论，Prrx1 刺激 Nrg1 的表达并促进心肌细胞增殖。总之，这些结果表明 Prrx1 是一种关键的转录因子，可平衡受伤斑马鱼心脏中的纤维化和再生。本文有一个相关的“论文背后的人物”访谈。
