Nutrient-sensing alteration leads to age-associated distortion of intestinal stem cell differentiating direction

IF 14.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Nature Communications Pub Date : 2024-10-25 DOI:10.1038/s41467-024-53675-7

Zihua Yu, Yuedan Zhu, Yi Chen, Chenxi Feng, Zehong Zhang, Xiaoxin Guo, Haiou Chen, Xingzhu Liu, Yu Yuan, Haiyang Chen

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Abstract

Nutrient-sensing pathways undergo deregulation in aged animals, exerting a pivotal role in regulating the cell cycle and subsequent stem cell division. Nevertheless, their precise functions in governing pluripotent stem cell differentiation remain largely elusive. Here, we uncovered a significant alteration in the cellular constituents of the intestinal epithelium in aged humans and mice. Employing Drosophila midgut and mouse organoid culture models, we made an observation regarding the altered trajectory of differentiation in intestinal stem cells (ISC) during overnutrition or aging, which stems from the erroneous activation of the insulin receptor signaling pathway. Through genetic analyses, we ascertained that the nutrient-sensing pathway regulated the direction of ISC differentiation by modulating the maturation of endosomes and SOX21A transcription factor. This study elucidates a nutrient-sensing pathway-mediated mechanism underlying stem cell differentiation, offering insights into the etiology of stem cell dysfunction in aged animals, including humans.

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营养传感的改变导致与年龄相关的肠干细胞分化方向的扭曲

营养传感途径在衰老动物体内发生失调，在调节细胞周期和随后的干细胞分裂中发挥着关键作用。然而，它们在调控多能干细胞分化方面的确切功能在很大程度上仍然难以捉摸。在这里，我们发现了老年人类和小鼠肠上皮细胞成分的显著变化。利用果蝇中肠和小鼠类器官培养模型，我们观察到肠道干细胞（ISC）在营养过剩或衰老过程中的分化轨迹发生了改变，这源于胰岛素受体信号通路的错误激活。通过基因分析，我们确定营养传感通路通过调节内体和SOX21A转录因子的成熟来调控肠干细胞的分化方向。这项研究阐明了营养传感通路介导的干细胞分化机制，为研究包括人类在内的老年动物干细胞功能障碍的病因提供了启示。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Nature Communications Biological Science Disciplines-

CiteScore

24.90

自引率

2.40%

发文量

6928

审稿时长

3.7 months

期刊介绍： Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.