A(∗)STAR Institute of Medical Biology, Singapore, Singapore; A(∗)STAR Institute of Molecular and Cell Biology, Singapore, Singapore.
A(∗)STAR Institute of Medical Biology, Singapore, Singapore; Section of Endocrinology & Investigative Medicine, Department of Metabolism, Digestion, and Reproduction, Imperial College London, London, UK.
Cell Rep. 2021 Jan 26;34(4):108633. doi: 10.1016/j.celrep.2020.108633.
Lgr5 crypt base columnar cells, the operational intestinal stem cells (ISCs), are thought to be dispensable for small intestinal (SI) homeostasis. Using a Lgr5-2A-DTR (diphtheria toxin receptor) model, which ablates Lgr5 cells with near-complete efficiency and retains endogenous levels of Lgr5 expression, we show that persistent depletion of Lgr5 ISCs in fact compromises SI epithelial integrity and reduces epithelial turnover in vivo. In vitro, Lgr5-2A-DTR SI organoids are unable to establish or survive when Lgr5 ISCs are continuously eliminated by adding DT to the media. However, transient exposure to DT at the start of culture allows organoids to form, and the rate of outgrowth reduces with the increasing length of DT presence. Our results indicate that intestinal homeostasis requires a constant pool of Lgr5 ISCs, which is supplied by rapidly reprogrammed non-Lgr5 crypt populations when preexisting Lgr5 ISCs are ablated.
Lgr5 隐窝柱状细胞是肠道干细胞（ISCs），被认为在小肠（SI）稳态中不是必需的。使用 Lgr5-2A-DTR（白喉毒素受体）模型，该模型以近乎完全的效率消除 Lgr5 细胞，同时保留内源性 Lgr5 表达水平，我们表明 Lgr5 ISC 的持续耗竭实际上会损害 SI 上皮完整性并减少体内上皮细胞的更新。在体外，当通过在培养基中添加 DT 持续消除 Lgr5 ISC 时，Lgr5-2A-DTR SI 类器官无法建立或存活。然而，在培养开始时短暂暴露于 DT 允许类器官形成，并且随着 DT 存在时间的延长，生长速度降低。我们的结果表明，肠道稳态需要一个恒定的 Lgr5 ISC 池，当预先存在的 Lgr5 ISC 被消除时，它由快速重编程的非 Lgr5 隐窝群体提供。
