Augmenting canonical Wnt signalling in therapeutically inert cells converts them into therapeutically potent exosome factories
Augmenting canonical Wnt signalling in therapeutically inert cells converts them into therapeutically potent exosome factories
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DOI：
10.1038/s41551-019-0448-6
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发表时间：
2019-09-01
影响因子：
28.1
通讯作者：
Marban, Eduardo
中科院分区：
文献类型：
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作者：
Ibrahim, Ahmed G. E.;Li, Chang;Marban, Eduardo
微球衍生的细胞是具有疾病修饰生物活性的治疗候选物，但它们的可变效力使它们的临床转化复杂化。来自人类供体的心球衍生细胞的转录组学分析揭示了它们的治疗效力与Wnt/β-连环蛋白信号传导和β-连环蛋白蛋白水平相关。在这里，我们表明，皮肤成纤维细胞工程过表达β-连环蛋白和转录因子Gata 4成为不朽和治疗有效。将工程化的成纤维细胞移植到急性心肌梗死的小鼠模型中导致心脏功能和小鼠存活率的改善，并且在杜氏肌营养不良症的mdx小鼠模型中，由工程化的成纤维细胞分泌的外泌体改善了运动能力并减少了肌肉纤维化。我们还证明，来自高效心球衍生细胞的外泌体表现出miR-92 a（Wnt/β-连环蛋白途径的已知增效剂）水平的提高，并且它们激活心肌细胞中的心脏保护性骨形态发生蛋白信号传导。我们的研究结果表明，经典Wnt信号转导的调节可以将治疗惰性的哺乳动物细胞转化为无细胞疗法的永生外泌体工厂。
Cardiosphere-derived cells are therapeutic candidates with disease-modifying bioactivity, but their variable potency has complicated their clinical translation. Transcriptomic analyses of cardiosphere-derived cells from human donors have revealed that their therapeutic potency correlates with Wnt/beta-catenin signalling and with beta-catenin protein levels. Here, we show that skin fibroblasts engineered to overexpress beta-catenin and the transcription factor Gata4 become immortal and therapeutically potent. Transplantation of the engineered fibroblasts into a mouse model of acute myocardial infarction led to improved cardiac function and mouse survival, and in the mdx mouse model of Duchenne muscular dystrophy, exosomes secreted by the engineered fibroblasts improved exercise capacity and reduced skeletal-muscle fibrosis. We also demonstrate that exosomes from high-potency cardiosphere-derived cells exhibit enhanced levels of miR-92a (a known potentiator of the Wnt/beta-catenin pathway), and that they activate cardioprotective bone-morphogenetic-protein signalling in cardiomyocytes. Our findings show that the modulation of canonical Wnt signalling can turn therapeutically inert mammalian cells into immortal exosome factories for cell-free therapies.