荷兰乌得勒支大学医学中心Maria J. Rodriguez Colman研究组合作取得最新进展。他们提出线粒体定义FOXO/Notch轴下游的肠道干细胞分化。这一研究成果发表在2020年11月3日出版的国际学术期刊《细胞-代谢》上。

他们显示线粒体活性支持基于隐窝的柱状细胞（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PC涉及向线粒体依赖性下调的新陈代谢转变。他们显示了叉头盒O（FoxO）转录因子和Notch信号在CBC命运决定中相互作用。与类器官数据一致，小鼠肠中Foxo1 / 3/4的缺失诱导了分泌细胞的分化。

重要的是，他们表明FOXO和Notch信号聚集在线粒体裂变的调控上，从而促使干细胞分化为杯状细胞和PC。最后，基于scRNA测序的CBC分化轨迹的重建支持FOXO、Notch和线粒体在分泌分化中的作用。总之，这指向了CBC分化中新的信号代谢轴，并强调了线粒体在决定干细胞命运中的重要性。

据了解，WNT和Notch差异信号调节Lgr5 + CBC向肠道细胞谱系的分化。

附：英文原文

Title: Mitochondria Define Intestinal Stem Cell Differentiation Downstream of a FOXO/Notch Axis

Author: Marlies C. Ludikhuize, Maaike Meerlo, Marc Pages Gallego, Despina Xanthakis, Mar Burgaya Julià, Nguyen T.B. Nguyen, Eline C. Brombacher, Nalan Liv, Madelon M. Maurice, Ji-hye Paik, Boudewijn M.T. Burgering, Maria J. Rodriguez Colman

Issue&Volume: 2020/11/03

Abstract: Differential WNT and Notch signaling regulates differentiation of Lgr5+ crypt-based columnar cells (CBCs) into intestinal cell lineages. Recently we showedthat mitochondrial activity supports CBCs, while adjacent Paneth cells (PCs) showreduced mitochondrial activity. This implies that CBC differentiation into PCs involvesa metabolic transition toward downregulation of mitochondrial dependency. Here weshow that Forkhead box O (FoxO) transcription factors and Notch signaling interactin 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 roleof FOXO, Notch, and mitochondria in secretory differentiation. Together, this pointsat a new signaling-metabolic axis in CBC differentiation and highlights the importanceof mitochondria in determining stem cell fate.

DOI: 10.1016/j.cmet.2020.10.005

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(20)30538-6