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

Zihua Yu, Yuedan Zhu, Yi Chen, Chenxi Feng, Zehong Zhang, Xiaoxin Guo, Haiou Chen, Xingzhu Liu, Yu Yuan and Haiyang Chen ()
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Zihua Yu: Sichuan University
Yuedan Zhu: Sichuan University
Yi Chen: Sichuan University
Chenxi Feng: Sichuan University
Zehong Zhang: Sichuan University
Xiaoxin Guo: Sichuan University
Haiou Chen: Sichuan University
Xingzhu Liu: Sichuan University
Yu Yuan: Sichuan University
Haiyang Chen: Sichuan University

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-53675-7

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