Transcriptome analysis reveals genes associated with stem cell activation by physical exercise in the dentate gyrus of aged p16Ink4a knockout mice

Frontiers in Cell and Developmental Biology

Cell and Developmental Biology

Nicola Ancona¹  Teresa Maria Creanza¹  Giorgio D'Andrea²  Laura Micheli²  Daniel Volpe²  Felice Tirone²  Raffaella Scardigli³ 

[1] CNR-Institute of Intelligent Industrial Technologies and Systems for Advanced Manufacturing, Bari, Italy;Institute of Biochemistry and Cell Biology, National Research Council, Rome, Italy;Institute of Translational Pharmacology, National Research Council, Rome, Italy;European Brain Research Institute (EBRI), Rome, Italy;

关键词: adult neurogenesis;    aging;    dentate gyrus;    neural stem cells;    self-renewal;    physical exercise;    running;    p16INK4a;   

DOI  :  10.3389/fcell.2023.1270892

 received in 2023-08-01, accepted in 2023-10-06,  发布年份 2023

来源: Frontiers

【 摘 要 】

Throughout adulthood neural stem cells divide in neurogenic niches–the dentate gyrus of the hippocampus and the subventricular zone–producing progenitor cells and new neurons. Stem cells self-renew, thus preserving their pool. Furthermore, the number of stem/progenitor cells in the neurogenic niches decreases with age. We have previously demonstrated that the cyclin-dependent kinase inhibitor p16Ink4a maintains, in aged mice, the pool of dentate gyrus stem cells by preventing their activation after a neurogenic stimulus such as exercise (running). We showed that, although p16Ink4a ablation by itself does not activate stem/progenitor cells, exercise strongly induced stem cell proliferation in p16Ink4a knockout dentate gyrus, but not in wild-type. As p16Ink4a regulates stem cell self-renewal during aging, we sought to profile the dentate gyrus transcriptome from p16Ink4a wild-type and knockout aged mice, either sedentary or running for 12 days. By pairwise comparisons of differentially expressed genes and by correlative analyses through the DESeq2 software, we identified genes regulated by p16Ink4a deletion, either without stimulus (running) added, or following running. The p16Ink4a knockout basic gene signature, i.e., in sedentary mice, involves upregulation of apoptotic, neuroinflammation- and synaptic activity-associated genes, suggesting a reactive cellular state. Conversely, another set of 106 genes we identified, whose differential expression specifically reflects the pattern of proliferative response of p16 knockout stem cells to running, are involved in processes that regulate stem cell activation, such as synaptic function, neurotransmitter metabolism, stem cell proliferation control, and reactive oxygen species level regulation. Moreover, we analyzed the regulation of these stem cell-specific genes after a second running stimulus. Surprisingly, the second running neither activated stem cell proliferation in the p16Ink4a knockout dentate gyrus nor changed the expression of these genes, confirming that they are correlated to the stem cell reactivity to stimulus, a process where they may play a role regulating stem cell activation.

【 授权许可】

Unknown   
Copyright © 2023 Micheli, D'Andrea, Creanza, Volpe, Ancona, Scardigli and Tirone.