Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland.
The David H. Koch Institute for Integrative Cancer Research at MIT, Department of Biology, MIT, Cambridge, MA, USA.
Nature. 2019 Jul;571(7765):398-402. doi: 10.1038/s41586-019-1383-0. Epub 2019 Jul 10.
A decline in stem cell function impairs tissue regeneration during ageing, but the role of the stem-cell-supporting niche in ageing is not well understood. The small intestine is maintained by actively cycling intestinal stem cells that are regulated by the Paneth cell niche. Here we show that the regenerative potential of human and mouse intestinal epithelium diminishes with age owing to defects in both stem cells and their niche. The functional decline was caused by a decrease in stemness-maintaining Wnt signalling due to production of Notum, an extracellular Wnt inhibitor, in aged Paneth cells. Mechanistically, high activity of mammalian target of rapamycin complex 1 (mTORC1) in aged Paneth cells inhibits activity of peroxisome proliferator activated receptor α (PPAR-α), and lowered PPAR-α activity increased Notum expression. Genetic targeting of Notum or Wnt supplementation restored function of aged intestinal organoids. Moreover, pharmacological inhibition of Notum in mice enhanced the regenerative capacity of aged stem cells and promoted recovery from chemotherapy-induced damage. Our results reveal a role of the stem cell niche in ageing and demonstrate that targeting of Notum can promote regeneration of aged tissues.
干细胞功能的衰退会损害衰老过程中的组织再生，但干细胞支持性龛在衰老中的作用还不是很清楚。小肠通过活跃循环的肠干细胞维持，这些干细胞受到潘氏细胞龛的调节。在这里，我们表明，由于年老的潘氏细胞中产生的细胞外 Wnt 抑制剂 Notum 导致 Wnt 信号维持干性的能力下降，人类和小鼠肠道上皮的再生潜力随着年龄的增长而降低。从机制上讲，年老的潘氏细胞中 mTORC1 的高活性抑制了过氧化物酶体增殖物激活受体α（PPAR-α）的活性，降低的 PPAR-α 活性增加了 Notum 的表达。Notum 或 Wnt 补充的基因靶向恢复了老年肠类器官的功能。此外，在小鼠中用药物抑制 Notum 增强了衰老干细胞的再生能力，并促进了化疗引起的损伤的恢复。我们的研究结果揭示了干细胞龛在衰老中的作用，并表明靶向 Notum 可以促进衰老组织的再生。
