Department of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Oncode Institute, Utrecht, The Netherlands.
Nature. 2022 Jul;607(7919):548-554. doi: 10.1038/s41586-022-04962-0. Epub 2022 Jul 13.
The morphology and functionality of the epithelial lining differ along the intestinal tract, but tissue renewal at all sites is driven by stem cells at the base of crypts. Whether stem cell numbers and behaviour vary at different sites is unknown. Here we show using intravital microscopy that, despite similarities in the number and distribution of proliferative cells with an Lgr5 signature in mice, small intestinal crypts contain twice as many effective stem cells as large intestinal crypts. We find that, although passively displaced by a conveyor-belt-like upward movement, small intestinal cells positioned away from the crypt base can function as long-term effective stem cells owing to Wnt-dependent retrograde cellular movement. By contrast, the near absence of retrograde movement in the large intestine restricts cell repositioning, leading to a reduction in effective stem cell number. Moreover, after suppression of the retrograde movement in the small intestine, the number of effective stem cells is reduced, and the rate of monoclonal conversion of crypts is accelerated. Together, these results show that the number of effective stem cells is determined by active retrograde movement, revealing a new channel of stem cell regulation that can be experimentally and pharmacologically manipulated.
沿着肠道，上皮衬里的形态和功能会有所不同，但所有部位的组织更新都是由隐窝底部的干细胞驱动的。不同部位的干细胞数量和行为是否存在差异尚不清楚。在这里，我们通过活体显微镜观察到，尽管在具有 Lgr5 特征的增殖细胞的数量和分布方面存在相似性，但小肠隐窝中的有效干细胞数量是大肠隐窝的两倍。我们发现，尽管小肠细胞会被传送带样的向上运动被动地推离，但由于 Wnt 依赖性的逆行细胞运动，远离隐窝底部的小肠细胞仍可以作为长期有效的干细胞发挥作用。相比之下，大肠中逆行运动的近乎缺失限制了细胞的重新定位，导致有效干细胞数量减少。此外，在抑制小肠中的逆行运动后，有效干细胞的数量减少，并且隐窝的单克隆转化率加快。这些结果表明，有效干细胞的数量是由活跃的逆行运动决定的，揭示了一种新的干细胞调控途径，可通过实验和药理学手段进行调控。
