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Engineering transplantable jejunal mucosal grafts using patient-derived organoids from children with intestinal failure.
Nature Medicine ( IF 58.7 ) Pub Date : 2020-09-07 , DOI: 10.1038/s41591-020-1024-z
Laween Meran 1, 2 , Isobel Massie 1 , Sara Campinoti 1, 2 , Anne E Weston 1 , Riana Gaifulina 3 , Lucinda Tullie 1, 2 , Peter Faull 1 , Michael Orford 2 , Anna Kucharska 1 , Anna Baulies 1 , Laura Novellasdemunt 1 , Nikolaos Angelis 1 , Elizabeth Hirst 1 , Julia König 1 , Alfonso Maria Tedeschi 2 , Alessandro Filippo Pellegata 2 , Susanna Eli 2 , Ambrosius P Snijders 1 , Lucy Collinson 1 , Nikhil Thapar 2, 4 , Geraint M H Thomas 3 , Simon Eaton 2 , Paola Bonfanti 1, 2 , Paolo De Coppi 2, 5 , Vivian S W Li 1
Affiliation  

Intestinal failure, following extensive anatomical or functional loss of small intestine, has debilitating long-term consequences for children1. The priority of patient care is to increase the length of functional intestine, particularly the jejunum, to promote nutritional independence2. Here we construct autologous jejunal mucosal grafts using biomaterials from pediatric patients and show that patient-derived organoids can be expanded efficiently in vitro. In parallel, we generate decellularized human intestinal matrix with intact nanotopography, which forms biological scaffolds. Proteomic and Raman spectroscopy analyses reveal highly analogous biochemical profiles of human small intestine and colon scaffolds, indicating that they can be used interchangeably as platforms for intestinal engineering. Indeed, seeding of jejunal organoids onto either type of scaffold reliably reconstructs grafts that exhibit several aspects of physiological jejunal function and that survive to form luminal structures after transplantation into the kidney capsule or subcutaneous pockets of mice for up to 2 weeks. Our findings provide proof-of-concept data for engineering patient-specific jejunal grafts for children with intestinal failure, ultimately aiding in the restoration of nutritional autonomy.



中文翻译:


使用来自肠衰竭儿童的患者来源的类器官设计可移植的空肠粘膜移植物。



小肠广泛的解剖学或功能丧失后的肠衰竭会给儿童带来长期的衰弱后果1 。患者护理的首要任务是增加功能性肠道(特别是空肠)的长度,以促进营养独立2 。在这里,我们使用儿科患者的生物材料构建自体空肠粘膜移植物,并表明患者来源的类器官可以在体外有效扩展。与此同时,我们生成具有完整纳米形貌的脱细胞人肠道基质,形成生物支架。蛋白质组学和拉曼光谱分析揭示了人类小肠和结肠支架高度相似的生化特征,表明它们可以互换用作肠道工程平台。事实上,将空肠类器官接种到任一类型的支架上都能可靠地重建移植物,这些移植物表现出生理空肠功能的多个方面,并且在移植到小鼠的肾囊或皮下袋中长达两周后能够存活形成管腔结构。我们的研究结果为针对肠道衰竭儿童设计患者特异性空肠移植物提供了概念验证数据,最终有助于恢复营养自主。

更新日期:2020-09-08
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