Division of Oncogenomics, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.
Nat Commun. 2022 Aug 2;13(1):4492. doi: 10.1038/s41467-022-32220-4.
The small intestine is a rapidly proliferating organ that is maintained by a small population of Lgr5-expressing intestinal stem cells (ISCs). However, several Lgr5-negative ISC populations have been identified, and this remarkable plasticity allows the intestine to rapidly respond to both the local environment and to damage. However, the mediators of such plasticity are still largely unknown. Using intestinal organoids and mouse models, we show that upon ribosome impairment (driven by Rptor deletion, amino acid starvation, or low dose cyclohexamide treatment) ISCs gain an Lgr5-negative, fetal-like identity. This is accompanied by a rewiring of metabolism. Our findings suggest that the ribosome can act as a sensor of nutrient availability, allowing ISCs to respond to the local nutrient environment. Mechanistically, we show that this phenotype requires the activation of ZAKɑ, which in turn activates YAP, via SRC. Together, our data reveals a central role for ribosome dynamics in intestinal stem cells, and identify the activation of ZAKɑ as a critical mediator of stem cell identity.
小肠是一个快速增殖的器官，由一小群表达 Lgr5 的肠干细胞（ISCs）维持。然而，已经鉴定出了几种 Lgr5 阴性的 ISC 群体，这种显著的可塑性允许肠道能够迅速响应局部环境和损伤。然而，这种可塑性的介质在很大程度上仍然未知。使用肠类器官和小鼠模型，我们表明，在核糖体受损（由 Rptor 缺失、氨基酸饥饿或低剂量环已酰胺处理驱动）时，ISCs 获得 Lgr5 阴性的胎儿样特征。这伴随着代谢的重新布线。我们的研究结果表明，核糖体可以作为营养可用性的传感器，使 ISCs 能够响应局部营养环境。从机制上讲，我们表明这种表型需要 ZAKɑ 的激活，ZAKɑ 通过 SRC 反过来激活 YAP。总之，我们的数据揭示了核糖体动力学在肠干细胞中的核心作用，并确定了 ZAKɑ 的激活是干细胞特征的关键介质。
