Huang Ying, Harrison Michael R, Osorio Arthela, Kim Jieun, Baugh Aaron, Duan Cunming, Sucov Henry M, Lien Ching-Ling
Heart Institute, The Saban Research Institute of Children's Hospital Los Angeles, Los Angeles, California, United States of America ; Program of Developmental Biology and Regenerative Medicine, The Saban Research Institute of Children's Hospital Los Angeles, Los Angeles, California, United States of America ; Craniofacial Biology Graduate Program, Ostrow School of Dentistry, University of Southern California, Los Angeles, California, United States of America.
PLoS One. 2013 Jun 26;8(6):e67266. doi: 10.1371/journal.pone.0067266. Print 2013.
Unlike its mammalian counterpart, the adult zebrafish heart is able to fully regenerate after severe injury. One of the most important events during the regeneration process is cardiomyocyte proliferation, which results in the replacement of lost myocardium. Growth factors that induce cardiomyocyte proliferation during zebrafish heart regeneration remain to be identified. Signaling pathways important for heart development might be reutilized during heart regeneration. IGF2 was recently shown to be important for cardiomyocyte proliferation and heart growth during mid-gestation heart development in mice, although its role in heart regeneration is unknown. We found that expression of igf2b was upregulated during zebrafish heart regeneration. Following resection of the ventricle apex, igf2b expression was detected in the wound, endocardium and epicardium at a time that coincides with cardiomyocyte proliferation. Transgenic zebrafish embryos expressing a dominant negative form of Igf1 receptor (dn-Igf1r) had fewer cardiomyocytes and impaired heart development, as did embryos treated with an Igf1r inhibitor. Moreover, inhibition of Igf1r signaling blocked cardiomyocyte proliferation during heart development and regeneration. We found that Igf signaling is required for a subpopulation of cardiomyocytes marked by gata4:EGFP to contribute to the regenerating area. Our findings suggest that Igf signaling is important for heart development and myocardial regeneration in zebrafish.
与哺乳动物不同，成年斑马鱼的心脏在受到严重损伤后能够完全再生。再生过程中最重要的事件之一是心肌细胞增殖，这导致丢失的心肌得以替换。在斑马鱼心脏再生过程中诱导心肌细胞增殖的生长因子仍有待确定。对心脏发育重要的信号通路在心脏再生过程中可能会被重新利用。最近有研究表明，IGF2在小鼠妊娠中期心脏发育过程中对心肌细胞增殖和心脏生长很重要，但其在心脏再生中的作用尚不清楚。我们发现，igf2b在斑马鱼心脏再生过程中表达上调。在切除心室尖端后，在伤口、心内膜和心外膜中检测到igf2b的表达，且此时与心肌细胞增殖时间一致。表达显性负性形式的Igf1受体（dn-Igf1r）的转基因斑马鱼胚胎心肌细胞较少且心脏发育受损，用Igf1r抑制剂处理的胚胎也是如此。此外，抑制Igf1r信号通路会阻碍心脏发育和再生过程中的心肌细胞增殖。我们发现，Igf信号通路对于以gata4:EGFP标记的心肌细胞亚群参与再生区域是必需的。我们的研究结果表明，Igf信号通路对斑马鱼的心脏发育和心肌再生很重要。
