The impact of telomere shortening on human hippocampal neurogenesis: Implications for cognitive function and psychiatric disorder risk
The impact of telomere shortening on human hippocampal neurogenesis: Implications for cognitive function and psychiatric disorder risk
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DOI：
10.1101/2020.04.19.049411
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发表时间：
2020-04
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影响因子：
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通讯作者：
A. Palmos;R. Duarte;Demelza M. Smeeth;Erin C. Hedges;D. Nixon;S. Thuret;T. Powell
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文献类型：
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作者：
A. Palmos;R. Duarte;Demelza M. Smeeth;Erin C. Hedges;D. Nixon;S. Thuret;T. Powell
端粒缩短是细胞衰老的一个标志，它可以限制细胞群的增殖能力，增加与年龄相关的疾病的风险。据推测，在精神障碍患者中，短端粒以及随后海马祖细胞的有限增殖能力可能导致海马体积较小和认知受损。本研究采用系统的、多学科的方法，旨在模拟端粒缩短对人类海马神经发生的影响，并探讨其与认知和精神疾病风险的关系。我们模拟端粒缩短人海马祖细胞在体外使用一系列传代协议，模仿末端复制的问题。老化的祖细胞表现出较短的端粒（p<0.05），并且细胞增殖速率降低，如溴脱氧尿苷染色所标记的（p<0.001），细胞分化成神经元或神经胶质的能力没有变化。RNA测序和基因集富集分析揭示了细胞衰老对与神经发生、端粒维持、细胞衰老和细胞因子产生相关的基因网络的影响。下调的转录物与调节认知功能和精神分裂症和双相情感障碍风险的基因有显著重叠。总的来说，我们的研究结果表明，端粒缩短引起的成年海马神经发生减少可能是导致年龄相关认知障碍和精神疾病风险的细胞机制。
Telomere shortening is one hallmark of cell ageing that can limit the proliferative capacity of cell populations and increase risk for age-related disease. It has been hypothesized that short telomeres, and subsequently a limited proliferative capacity of hippocampal progenitor cells, could contribute to smaller hippocampal volumes and impaired cognition, amongst psychiatric disorder patients. The current study employed a systematic, multidisciplinary approach which aimed to model the effects of telomere shortening on human hippocampal neurogenesis, and to explore its relationship with cognition and psychiatric disorder risk. We modelled telomere shortening in human hippocampal progenitor cells in vitro using a serial passaging protocol that mimics the end-replication problem. Aged progenitors demonstrated shorter telomeres (p<0.05), and reduced rates of cell proliferation, as marked by bromodeoxyuridine staining (p<0.001), with no changes in the ability of cells to differentiate into neurons or glia. RNA-sequencing and gene set enrichment analysis revealed an effect of cell ageing on gene networks related to neurogenesis, telomere maintenance, cell senescence and cytokine production. Downregulated transcripts showed a significant overlap with genes regulating cognitive function and risk for schizophrenia and bipolar disorder. Collectively, our results suggest that reductions in adult hippocampal neurogenesis, caused by telomere shortening, could represent a cellular mechanism contributing to age-related cognitive impairment and psychiatric disorder risk.