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, Haiyang Chen

West China Centre of Excellence for Pancreatitis and Laboratory of Stem Cell and Anti-Aging Research, Frontiers Science Center for Disease-related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China. · pubmed

Paper

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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Research summary

The paper investigates the role of nutrient-sensing pathways in the differentiation of intestinal stem cells, particularly in the context of aging. This focus on the mechanisms underlying stem cell dysfunction in aged organisms aligns with longevity research, as it addresses potential root causes of age-related decline in stem cell function. However, while the findings are solid and contribute to our understanding of aging processes, they do not present groundbreaking insights that would significantly alter the field, hence the moderate impact score.

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