Homeostatic mini-intestines through scaffold-guided organoid morphogenesis
Homeostatic mini-intestines through scaffold-guided organoid morphogenesis
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DOI：
10.1038/s41586-020-2724-8
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发表时间：
2020-09-16
期刊：
影响因子：
64.8
通讯作者：
Lutolf, Matthias P.
中科院分区：
文献类型：
--
作者：
Nikolaev, Mikhail;Mitrofanova, Olga;Lutolf, Matthias P.
上皮类器官，如来源于肠干细胞的类器官，具有建模组织和疾病生物学的巨大潜力（1-4）。然而，目前用于在三维基质中衍生这些类器官的方法（5，6）导致随机发育的组织具有封闭的囊性结构，其限制了寿命和大小，限制了实验操作并禁止了体内平衡。在这里，通过使用组织工程和细胞的内在自组织特性，我们诱导肠干细胞形成管状上皮细胞，其具有可进入的管腔和与体内类似的隐窝和绒毛样结构域的空间排列。当连接到外部泵送系统时，微肠管是可灌注的;这允许连续去除死细胞以将组织寿命延长数周，并且还使得管能够被微生物定殖以模拟宿主-微生物相互作用。小肠包括在传统类器官中很少发现的罕见的专门细胞类型。它们保留了肠道的关键生理特征，并具有显著的再生能力。我们从外部引导干细胞自组织成功能性芯片上类器官的概念具有广泛的适用性，并且将能够获得更具生理相关性的类器官形状、大小和功能。
Epithelial organoids, such as those derived from stem cells of the intestine, have great potential for modelling tissue and disease biology(1-4). However, the approaches that are used at present to derive these organoids in three-dimensional matrices(5,6)result in stochastically developing tissues with a closed, cystic architecture that restricts lifespan and size, limits experimental manipulation and prohibits homeostasis. Here, by using tissue engineering and the intrinsic self-organization properties of cells, we induce intestinal stem cells to form tube-shaped epithelia with an accessible lumen and a similar spatial arrangement of crypt- and villus-like domains to that in vivo. When connected to an external pumping system, the mini-gut tubes are perfusable; this allows the continuous removal of dead cells to prolong tissue lifespan by several weeks, and also enables the tubes to be colonized with microorganisms for modelling host-microorganism interactions. The mini-intestines include rare, specialized cell types that are seldom found in conventional organoids. They retain key physiological hallmarks of the intestine and have a notable capacity to regenerate. Our concept for extrinsically guiding the self-organization of stem cells into functional organoids-on-a-chip is broadly applicable and will enable the attainment of more physiologically relevant organoid shapes, sizes and functions.