美国斯坦福大学Anne Brunet研究组报道，空间转录组时钟揭示了大脑衰老过程中的细胞临近效应。相关论文发表在2024年12月18日出版的《自然》杂志上。

据悉，老年与认知功能下降和神经退行性疾病风险增加有关。大脑老化是复杂的，伴随着许多细胞的变化。此外，衰老细胞对邻近细胞的影响，以及这种影响如何导致组织衰退尚不清楚。更一般地说，在老化组织中系统地解决这个问题的工具尚未开发出来。

该课题组人员生成了一个空间分辨率的单细胞转录组大脑图谱，涵盖了从成年生命周期中20个不同年龄段的420万个细胞，以及两种年轻化干预措施——运动和部分重编程。小组建立了空间衰老时钟，这是一种在空间转录组图谱上训练的机器学习模型，用以识别衰老、年轻化和疾病的空间和细胞类型特异性的转录组特征，包括罕见细胞类型的特征。

利用空间衰老时钟和深度学习，研究组发现随着年龄的增长，T细胞越来越多地渗入大脑，对邻近细胞具有显著的促衰老邻近效应。令人惊讶的是，神经干细胞对邻近细胞有很强的促恢复作用。

该研究组还确定了T细胞的促衰老作用，和神经干细胞对其邻近细胞的促恢复作用的潜在介质。这些结果表明，罕见的细胞类型可以对它们的邻居产生强有力的影响，并可能成为对抗组织衰老的目标。空间衰老时钟是研究空间背景下细胞-细胞相互作用的重要工具，应该允许对衰老和疾病干预措施的有效性进行可扩展评估。

附：英文原文

Title: Spatial transcriptomic clocks reveal cell proximity effects in brain ageing

Author: Sun, Eric D., Zhou, Olivia Y., Hauptschein, Max, Rappoport, Nimrod, Xu, Lucy, Navarro Negredo, Paloma, Liu, Ling, Rando, Thomas A., Zou, James, Brunet, Anne

Issue&Volume: 2024-12-18

Abstract: Old age is associated with a decline in cognitive function and an increase in neurodegenerative disease risk1. Brain ageing is complex and is accompanied by many cellular changes2. Furthermore, the influence that aged cells have on neighbouring cells and how this contributes to tissue decline is unknown. More generally, the tools to systematically address this question in ageing tissues have not yet been developed. Here we generate a spatially resolved single-cell transcriptomics brain atlas of 4.2 million cells from 20 distinct ages across the adult lifespan and across two rejuvenating interventions—exercise and partial reprogramming. We build spatial ageing clocks, machine learning models trained on this spatial transcriptomics atlas, to identify spatial and cell-type-specific transcriptomic fingerprints of ageing, rejuvenation and disease, including for rare cell types. Using spatial ageing clocks and deep learning, we find that T cells, which increasingly infiltrate the brain with age, have a marked pro-ageing proximity effect on neighbouring cells. Surprisingly, neural stem cells have a strong pro-rejuvenating proximity effect on neighbouring cells. We also identify potential mediators of the pro-ageing effect of T cells and the pro-rejuvenating effect of neural stem cells on their neighbours. These results suggest that rare cell types can have a potent influence on their neighbours and could be targeted to counter tissue ageing. Spatial ageing clocks represent a useful tool for studying cell–cell interactions in spatial contexts and should allow scalable assessment of the efficacy of interventions for ageing and disease.

DOI: 10.1038/s41586-024-08334-8

Source: https://www.nature.com/articles/s41586-024-08334-8