Institute for Biochemistry and Molecular Biology, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany.
Hubrecht Institute, University Medical Centre Utrecht, Uppsalaan 8, 3584 CT Utrecht, the Netherlands.
Dev Cell. 2016 Jan 11;36(1):36-49. doi: 10.1016/j.devcel.2015.12.010. Epub 2015 Dec 31.
In contrast to mammals, zebrafish regenerate heart injuries via proliferation of cardiomyocytes located near the wound border. To identify regulators of cardiomyocyte proliferation, we used spatially resolved RNA sequencing (tomo-seq) and generated a high-resolution genome-wide atlas of gene expression in the regenerating zebrafish heart. Interestingly, we identified two wound border zones with distinct expression profiles, including the re-expression of embryonic cardiac genes and targets of bone morphogenetic protein (BMP) signaling. Endogenous BMP signaling has been reported to be detrimental to mammalian cardiac repair. In contrast, we find that genetic or chemical inhibition of BMP signaling in zebrafish reduces cardiomyocyte dedifferentiation and proliferation, ultimately compromising myocardial regeneration, while bmp2b overexpression is sufficient to enhance it. Our results provide a resource for further studies on the molecular regulation of cardiac regeneration and reveal intriguing differential cellular responses of cardiomyocytes to a conserved signaling pathway in regenerative versus non-regenerative hearts.
与哺乳动物不同，斑马鱼通过位于伤口边缘附近的心肌细胞增殖来再生心脏损伤。为了鉴定心肌细胞增殖的调节因子，我们使用空间分辨 RNA 测序（tomo-seq）技术，生成了再生斑马鱼心脏的高分辨率全基因组表达图谱。有趣的是，我们鉴定出了两个具有不同表达谱的伤口边缘区，包括胚胎心脏基因的重新表达和骨形态发生蛋白 (BMP) 信号的靶基因。内源性 BMP 信号已被报道对哺乳动物心脏修复有害。相比之下，我们发现，在斑马鱼中抑制 BMP 信号的遗传或化学方法会减少心肌细胞去分化和增殖，最终损害心肌再生，而过表达 bmp2b 则足以增强心肌再生。我们的研究结果为进一步研究心脏再生的分子调控提供了资源，并揭示了在再生和非再生心脏中，心肌细胞对保守信号通路的细胞反应存在有趣的差异。
