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Augmenting canonical Wnt signalling in therapeutically inert cells converts them into therapeutically potent exosome factories.
Nature Biomedical Engineering ( IF 26.8 ) Pub Date : 2019-08-26 , DOI: 10.1038/s41551-019-0448-6 Ahmed G E Ibrahim 1, 2 , Chang Li , Russel Rogers 1 , Mario Fournier 1 , Liang Li 2 , Sharon D Vaturi 2 , Travis Antes 1 , Lizbeth Sanchez 1 , Akbarshakh Akhmerov 1 , Jennifer Johnson Moseley 2 , Brooke Tobin 2 , Luis Rodriguez-Borlado 2 , Rachel R Smith 2 , Linda Marbán 2 , Eduardo Marbán 1
Nature Biomedical Engineering ( IF 26.8 ) Pub Date : 2019-08-26 , DOI: 10.1038/s41551-019-0448-6 Ahmed G E Ibrahim 1, 2 , Chang Li , Russel Rogers 1 , Mario Fournier 1 , Liang Li 2 , Sharon D Vaturi 2 , Travis Antes 1 , Lizbeth Sanchez 1 , Akbarshakh Akhmerov 1 , Jennifer Johnson Moseley 2 , Brooke Tobin 2 , Luis Rodriguez-Borlado 2 , Rachel R Smith 2 , Linda Marbán 2 , Eduardo Marbán 1
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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/β-catenin signalling and with β-catenin protein levels. Here, we show that skin fibroblasts engineered to overexpress β-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/β-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.
中文翻译：
在治疗惰性细胞中增强规范性Wnt信号转导将其转化为治疗有效的外泌体工厂。
心球来源的细胞是具有疾病修饰生物活性的治疗候选物，但其可变效能使它们的临床翻译变得复杂。对来自人类供体的心脏层细胞的转录组学分析表明，其治疗功效与Wnt /β-catenin信号传导以及β-catenin蛋白水平相关。在这里，我们表明，工程改造为过度表达β-catenin和转录因子Gata4的皮肤成纤维细胞具有无限的治疗潜力。将工程纤维母细胞移植到急性心肌梗塞的小鼠模型中可改善心脏功能和小鼠存活率，而在Duchenne肌营养不良症的mdx小鼠模型中，工程纤维母细胞分泌的外泌体可改善运动能力并减少骨骼肌纤维化。我们还证明了来自高能心球来源细胞的外泌体表现出增强的miR-92a水平（Wnt /β-catenin途径的已知增强剂），并且它们激活了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，规范的Wnt信号转导可以将治疗惰性的哺乳动物细胞转变为永生的外泌体工厂，以进行无细胞治疗。
更新日期：2019-08-27
中文翻译：
在治疗惰性细胞中增强规范性Wnt信号转导将其转化为治疗有效的外泌体工厂。
心球来源的细胞是具有疾病修饰生物活性的治疗候选物，但其可变效能使它们的临床翻译变得复杂。对来自人类供体的心脏层细胞的转录组学分析表明，其治疗功效与Wnt /β-catenin信号传导以及β-catenin蛋白水平相关。在这里，我们表明，工程改造为过度表达β-catenin和转录因子Gata4的皮肤成纤维细胞具有无限的治疗潜力。将工程纤维母细胞移植到急性心肌梗塞的小鼠模型中可改善心脏功能和小鼠存活率，而在Duchenne肌营养不良症的mdx小鼠模型中，工程纤维母细胞分泌的外泌体可改善运动能力并减少骨骼肌纤维化。我们还证明了来自高能心球来源细胞的外泌体表现出增强的miR-92a水平（Wnt /β-catenin途径的已知增强剂），并且它们激活了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，规范的Wnt信号转导可以将治疗惰性的哺乳动物细胞转变为永生的外泌体工厂，以进行无细胞治疗。
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