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Is zebrafish heart regeneration “complete”? Lineage-restricted cardiomyocytes proliferate to pre-injury numbers but some fail to differentiate in fibrotic hearts
Developmental Biology ( IF 2.7 ) Pub Date : 2020-12-10 , DOI: 10.1016/j.ydbio.2020.12.004
Alberto Bertozzi 1 , Chi-Chung Wu 1 , Phong D Nguyen 2 , Mohankrishna Dalvoy Vasudevarao 1 , Medhanie A Mulaw 3 , Charlotte D Koopman 4 , Teun P de Boer 5 , Jeroen Bakkers 4 , Gilbert Weidinger 1
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Adult zebrafish are frequently described to be able to “completely” regenerate the heart. Yet, the extent to which cardiomyocytes lost to injury are replaced is unknown, since existing evidence for cardiomyocyte proliferation is indirect or non-quantitative. We established stereological methods to quantify the number of cardiomyocytes at several time-points post cryoinjury. Intriguingly, after cryoinjuries that killed about 1/3 of the ventricular cardiomyocytes, pre-injury cardiomyocyte numbers were restored already within 30 days. Yet, many hearts retained small residual scars, and a subset of cardiomyocytes bordering these fibrotic areas remained smaller, lacked differentiated sarcomeric structures, and displayed defective calcium signaling. Thus, a subset of regenerated cardiomyocytes failed to fully mature. While lineage-tracing experiments have shown that regenerating cardiomyocytes are derived from differentiated cardiomyocytes, technical limitations have previously made it impossible to test whether cardiomyocyte trans-differentiation contributes to regeneration of non-myocyte cell lineages. Using Cre responder lines that are expressed in all major cell types of the heart, we found no evidence for cardiomyocyte transdifferentiation into endothelial, epicardial, fibroblast or immune cell lineages. Overall, our results imply a refined answer to the question whether zebrafish can completely regenerate the heart: in response to cryoinjury, preinjury cardiomyocyte numbers are indeed completely regenerated by proliferation of lineage-restricted cardiomyocytes, while restoration of cardiomyocyte differentiation and function, as well as resorption of scar tissue, is less robustly achieved.



中文翻译:

斑马鱼心脏再生是否“完整”?受谱系限制的心肌细胞增生至损伤前的数量,但有些无法在纤维化心脏中分化

成年斑马鱼经常被描述为能够“完全”再生心脏。然而,由于受损的心肌细胞增殖的现有证据是间接的或非定量的,因此丢失受损的心肌细胞的替换程度尚不清楚。我们建立了立体方法来量化冷冻伤后几个时间点的心肌细胞数量。有趣的是,冷冻损伤杀死了约1/3的心室心肌细胞后,损伤前的心肌细胞数量已在30天内恢复。然而,许多心脏保留了小的残留疤痕,与这些纤维化区域接壤的一部分心肌细胞仍然较小,缺乏分化的肌节结构,并显示出有缺陷的钙信号传导。因此,一部分再生的心肌细胞不能完全成熟。虽然谱系追踪实验表明再生的心肌细胞来源于分化的心肌细胞,但技术限制以前无法测试心肌细胞的转分化是否有助于非心肌细胞谱系的再生。使用在心脏的所有主要细胞类型中表达的Cre应答细胞系,我们没有发现心肌细胞转分化为内皮细胞,心外膜细胞,成纤维细胞或免疫细胞系的证据。总体而言,我们的结果暗示着斑马鱼是否可以完全再生心脏这一问题的精妙答案:响应冷冻损伤,确实可以通过谱系限制型心肌细胞的增殖来完全再生损伤前心肌细胞的数量,同时恢复心肌细胞的分化和功能,

更新日期:2020-12-28
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