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, Yuan Yu, Haiyang Chen, Haiyang Chen, Haiyang Chen
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. Nutrient-sensing pathways undergo deregulation in aged animals. Here the authors uncover a significant alteration in the composition of intestinal epithelial cells during aging which is caused by changes to the differentiation direction of intestinal stem cells.