An organoid-based organ-repurposing approach to treat short bowel syndrome
An organoid-based organ-repurposing approach to treat short bowel syndrome
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DOI：
10.1038/s41586-021-03247-2
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发表时间：
2021-02-24
期刊：
影响因子：
64.8
通讯作者：
Sato, Toshiro
中科院分区：
文献类型：
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作者：
Sugimoto, Shinya;Kobayashi, Eiji;Sato, Toshiro
小肠是营养吸收的主要器官，其广泛切除导致吸收不良和消耗性疾病，称为短肠综合征（SBS）。类器官技术能够在体外有效扩增肠上皮组织（1），但重建整个小肠，包括复杂的淋巴血管系统，仍然具有挑战性（2）。在这里，我们通过用回肠衍生的类器官替代天然结肠上皮来产生功能性小结肠化结肠（SIC）。我们首先发现异种移植的人回肠类器官保持其区域身份并在小鼠结肠中形成新生绒毛结构。类器官单层的体外培养进一步揭示了腔机械流在绒毛形成中的重要作用。然后，我们通过将SIC重新定位在回盲部连接处来开发大鼠SIC模型，在回盲部连接处，上皮暴露于恒定的肠液腔流。这种解剖学上的重新定位为SIC提供了小肠的器官结构，包括完整的脉管系统和神经支配、绒毛结构和乳管（小肠特有的吸收脂肪的淋巴结构）。SIC具有吸收功能并显著改善SBS大鼠模型中的肠衰竭，而结肠类器官而不是回肠类器官的移植总是导致死亡。这些数据为肠类器官用于再生目的提供了原理证明，并为SBS治疗提供了可行的策略。
The small intestine is the main organ for nutrient absorption, and its extensive resection leads to malabsorption and wasting conditions referred to as short bowel syndrome (SBS). Organoid technology enables an efficient expansion of intestinal epithelium tissue in vitro(1), but reconstruction of the whole small intestine, including the complex lymphovascular system, has remained challenging(2). Here we generate a functional small intestinalized colon (SIC) by replacing the native colonic epithelium with ileum-derived organoids. We first find that xenotransplanted human ileum organoids maintain their regional identity and form nascent villus structures in the mouse colon. In vitro culture of an organoid monolayer further reveals an essential role for luminal mechanistic flow in the formation of villi. We then develop a rat SIC model by repositioning the SIC at the ileocaecal junction, where the epithelium is exposed to a constant luminal stream of intestinal juice. This anatomical relocation provides the SIC with organ structures of the small intestine, including intact vasculature and innervation, villous structures, and the lacteal (a fat-absorbing lymphatic structure specific to the small intestine). The SIC has absorptive functions and markedly ameliorates intestinal failure in a rat model of SBS, whereas transplantation of colon organoids instead of ileum organoids invariably leads to mortality. These data provide a proof of principle for the use of intestinal organoids for regenerative purposes, and offer a feasible strategy for SBS treatment.