Discovering small molecules as Wnt inhibitors that promote heart regeneration and injury repair
Discovering small molecules as Wnt inhibitors that promote heart regeneration and injury repair
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发现小分子作为 Wnt 抑制剂，促进心脏再生和损伤修复
DOI：
10.1093/jmcb/mjz023
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发表时间：
2019-03
影响因子：
5.5
通讯作者：
Zhong Tao P.
中科院分区：
文献类型：
--
作者：
Xie Shuying;Fu Wenbin;Yu Guangju;Hu Xueli;Lai Kaa Seng;Peng Xiangwen;Zhou Yating;Zhu Xuejiao;Christov Plamen;Sawyer Leah;Ni Terri T.;Sulikowski Gary A.;Yang Zhongzhou;Lee Ethan;Zeng Chunyu;Wang Wei E.;Zhong Tao P.
摘要 人们对发现可以促进心脏分化和再生以及修复受损心脏组织的再生医学先导物产生了浓厚的兴趣。我们将基于斑马鱼胚胎的筛选与心肌发生测定相结合，以发现能够调节心脏发育和再生且副作用最小的选择性小分子。两种具有新颖结构的相关化合物被命名为 Cardiomogen 1 和 2（CDMG1 和 CDMG2），因其通过扩大心脏祖细胞群而促进心肌增生的能力而被鉴定。我们发现 Cardiomogen 通过靶向 β-catenin 并减少培养细胞中 Tcf/Lef 介导的转录来充当 Wnt 抑制剂。 CDMG 治疗斑马鱼截肢心脏可减少受损心脏组织中的核 β-连环蛋白，增加心肌细胞 (CM) 增殖，并加速伤口愈合，从而加速心肌再生。重要的是，Cardiomogen 可以缓解心肌梗塞后哺乳动物心脏功能的恶化。暴露于 CDMG1 的受伤心脏显示出新形成的 CM 增加和纤维化疤痕组织减少，这部分归因于 β-连环蛋白的减少。我们的研究结果表明 Cardiomogen 作为 Wnt 抑制剂可增强损伤诱导的 CM 增殖和心脏再生，强调了基于胚胎的小分子筛选在发现有效且安全的药物先导物方面的价值。
Abstract There are intense interests in discovering proregenerative medicine leads that can promote cardiac differentiation and regeneration, as well as repair damaged heart tissues. We have combined zebrafish embryo-based screens with cardiomyogenesis assays to discover selective small molecules that modulate heart development and regeneration with minimal adverse effects. Two related compounds with novel structures, named as Cardiomogen 1 and 2 (CDMG1 and CDMG2), were identified for their capacity to promote myocardial hyperplasia through expansion of the cardiac progenitor cell population. We find that Cardiomogen acts as a Wnt inhibitor by targeting β-catenin and reducing Tcf/Lef-mediated transcription in cultured cells. CDMG treatment of amputated zebrafish hearts reduces nuclear β-catenin in injured heart tissue, increases cardiomyocyte (CM) proliferation, and expedites wound healing, thus accelerating cardiac muscle regeneration. Importantly, Cardiomogen can alleviate the functional deterioration of mammalian hearts after myocardial infarction. Injured hearts exposed to CDMG1 display increased newly formed CMs and reduced fibrotic scar tissue, which are in part attributable to the β-catenin reduction. Our findings indicate Cardiomogen as a Wnt inhibitor in enhancing injury-induced CM proliferation and heart regeneration, highlighting the values of embryo-based small molecule screens in discovery of effective and safe medicine leads.
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