Molecular Cancer Research, Center Molecular Medicine, University Medical Center Utrecht, Heidelberglaan 100, 3584 CG Utrecht, the Netherlands.
Department of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Heidelberglaan 100, 3584 CG Utrecht, the Netherlands.
Cell Metab. 2020 Nov 3;32(5):889-900.e7. doi: 10.1016/j.cmet.2020.10.005.
Differential WNT and Notch signaling regulates differentiation of Lgr5 crypt-based columnar cells (CBCs) into intestinal cell lineages. Recently we showed that mitochondrial activity supports CBCs, while adjacent Paneth cells (PCs) show reduced mitochondrial activity. This implies that CBC differentiation into PCs involves a metabolic transition toward downregulation of mitochondrial dependency. Here we show that Forkhead box O (FoxO) transcription factors and Notch signaling interact in determining CBC fate. In agreement with the organoid data, Foxo1/3/4 deletion in mouse intestine induces secretory cell differentiation. Importantly, we show that FOXO and Notch signaling converge on regulation of mitochondrial fission, which in turn provokes stem cell differentiation into goblet cells and PCs. Finally, scRNA-seq-based reconstruction of CBC differentiation trajectories supports the role of FOXO, Notch, and mitochondria in secretory differentiation. Together, this points at a new signaling-metabolic axis in CBC differentiation and highlights the importance of mitochondria in determining stem cell fate.
WNT 和 Notch 信号的差异调节 Lgr5 隐窝基柱状细胞（CBC）分化为肠细胞谱系。最近我们表明，线粒体活性支持 CBC，而相邻的 Paneth 细胞（PC）显示线粒体活性降低。这意味着 CBC 分化为 PCs 涉及代谢向降低线粒体依赖性的转变。在这里，我们表明 Forkhead box O (FoxO) 转录因子和 Notch 信号在决定 CBC 命运方面相互作用。与类器官数据一致，Foxo1/3/4 在小鼠肠道中的缺失诱导分泌细胞分化。重要的是，我们表明 FOXO 和 Notch 信号通路都集中在调节线粒体分裂上，这反过来又促使干细胞分化为杯状细胞和 PCs。最后，基于 scRNA-seq 的 CBC 分化轨迹重建支持 FOXO、Notch 和线粒体在分泌分化中的作用。总之，这表明在 CBC 分化中存在一个新的信号代谢轴，并强调了线粒体在决定干细胞命运中的重要性。
