Yap-dependent reprogramming of Lgr5+ stem cells drives intestinal regeneration and cancer
Yap-dependent reprogramming of Lgr5+ stem cells drives intestinal regeneration and cancer
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DOI：
10.1038/nature15382
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发表时间：
2015-10-29
期刊：
影响因子：
64.8
通讯作者：
Wrana, Jeffrey L.
中科院分区：
文献类型：
--
作者：
Gregorieff, Alex;Liu, Yu;Wrana, Jeffrey L.
肠上皮具有显著的自我更新能力，在稳态条件下，这种能力是由Wnt信号在Lgr5(+)肠干细胞(ISCs)中驱动的。然而，损伤后ISC再生的机制仍然知之甚少。河马信号通路调节组织生长，对再生很重要(2，3)。在这里，我们在小鼠身上证明了YAP，河马的下游转录效应因子，对于暴露于电离辐射后的肠道上皮细胞的恢复至关重要。YAP通过抑制Wnt信号和过度的Paneth细胞分化，短暂地重新编程Lgr5(+)ISCs，同时促进细胞存活，并诱导包括EGF途径激活的再生程序。因此，缺乏YAP的有机体的生长可以被EGFR配体表观调节素拯救，我们发现非细胞自主产生的间质表观调节素可以补偿体内YAP的损失。与再生信号在肿瘤发生中的关键作用一致，我们进一步证明了YAP失活可以消除APC(Min)小鼠结肠癌模型中的腺瘤，并且YAP驱动的APC(-/-)有机物的扩张需要YAP再生程序的EGFR模块。最后，我们在体内证明了YAP是早期APC突变的肿瘤启动细胞发展所必需的，它抑制了它们向Paneth细胞的分化，并诱导了再生程序和EGFR信号转导。我们的研究表明，在组织损伤后，YAP通过抑制Wnt稳态程序来重新编程Lgr5(+)ISCs，同时诱导包括激活EGFR信号的再生程序。此外，我们的发现揭示了YAP再生途径在驱动癌症启动中的关键作用。
The gut epithelium has remarkable self-renewal capacity that under homeostatic conditions is driven by Wnt signalling hi Lgr5(+) intestinal stem cells (ISCs)(1). However, the mechanisms underlying ISC regeneration after injury remain poorly understood. The Hippo signalling pathway mediates tissue growth and is important for regeneration(2,3). Here we demonstrate in mice that Yap, a downstream transcriptional effector of Hippo, is critical for recovery of intestinal epithelium after exposure to ionizing radiation. Yap transiently reprograms Lgr5(+) ISCs by suppressing Wnt signalling and excessive Paneth cell differentiation, while promoting cell survival and inducing a regenerative program that includes Egf pathway activation. Accordingly, growth of Yap-deficient organoids is rescued by the Egfr ligand epiregulin, and we find that non-cell-autonomous production of stromal epiregulin may compensate for Yap loss in vivo. Consistent with key roles for regenerative signalling in tumorigenesis, we further demonstrate that Yap inactivation abolishes adenomas in the Apc(Min) mouse model of colon cancer, and that Yap-driven expansion of Apc(-/-) organoids requires the Egfr module of the Yap regenerative program. Finally, we show that in vivo Yap is required for progression of early Apc mutant tumour-initiating cells, suppresses their differentiation into Paneth cells, and induces a regenerative program and Egfr signalling. Our studies reveal that upon tissue injury, Yap reprograms Lgr5(+) ISCs by inhibiting the Wnt homeostatic program, while inducing a regenerative program that includes activation of Egfr signalling. Moreover, our findings reveal a key role for the Yap regenerative pathway in driving cancer initiation.