Department of Genetics, Stanford University, Stanford, CA, USA.
Department of Biology, Stanford University, Stanford, CA, USA.
Nat Aging. 2024 Apr;4(4):546-567. doi: 10.1038/s43587-024-00594-3. Epub 2024 Mar 29.
Partial reprogramming (pulsed expression of reprogramming transcription factors) improves the function of several tissues in old mice. However, it remains largely unknown how partial reprogramming impacts the old brain. Here we use single-cell transcriptomics to systematically examine how partial reprogramming influences the subventricular zone neurogenic niche in aged mouse brains. Whole-body partial reprogramming mainly improves neuroblasts (cells committed to give rise to new neurons) in the old neurogenic niche, restoring neuroblast proportion to more youthful levels. Interestingly, targeting partial reprogramming specifically to the neurogenic niche also boosts the proportion of neuroblasts and their precursors (neural stem cells) in old mice and improves several molecular signatures of aging, suggesting that the beneficial effects of reprogramming are niche intrinsic. In old neural stem cell cultures, partial reprogramming cell autonomously restores the proportion of neuroblasts during differentiation and blunts some age-related transcriptomic changes. Importantly, partial reprogramming improves the production of new neurons in vitro and in old brains. Our work suggests that partial reprogramming could be used to rejuvenate the neurogenic niche and counter brain decline in old individuals.
部分重编程(重编程转录因子的脉冲表达)可改善老年小鼠几种组织的功能。然而,部分重编程如何影响老年大脑在很大程度上仍不清楚。在这里,我们使用单细胞转录组学系统地研究了部分重编程如何影响老年小鼠大脑的侧脑室神经发生龛。全身部分重编程主要改善老年神经发生龛中的神经母细胞(分化为新神经元的细胞),将神经母细胞的比例恢复到更年轻的水平。有趣的是,将部分重编程专门靶向神经发生龛也能提高老年小鼠神经母细胞及其前体细胞(神经干细胞)的比例,并改善几种衰老的分子特征,这表明重编程的有益效果是内在的。在老年神经干细胞培养物中,部分重编程在分化过程中自主恢复神经母细胞的比例,并减弱一些与年龄相关的转录组变化。重要的是,部分重编程可改善体外和老年大脑中新神经元的产生。我们的工作表明,部分重编程可用于恢复神经发生龛并对抗老年个体的大脑衰退。