CHIT1-positive microglia drive motor neuron ageing in the primate spinal cord

Shuhui Sun, Jiaming Li, Si Wang, Jingyi Li, Jie Ren, Zhaoshi Bao, Le Sun, Xibo Ma, Fangshuo Zheng, Shuai Ma, Liang Sun, Min Wang, Yan Yu, Miyang Ma, Qiaoran Wang, Zhiyuan Chen, He Ma, Xuebao Wang, Zeming Wu, Hui Zhang, Kaowen Yan, Yuanhan Yang, Yixin Zhang, Sheng Zhang, Jinghui Lei, Zhao-Qian Teng, Chang-Mei Liu, Ge Bai, Yan-Jiang Wang, Jian Li, Xiaoqun Wang, Guoguang Zhao, Tao Jiang, Juan Carlos Izpisua Belmonte, Jing Qu (), Weiqi Zhang () and Guang-Hui Liu ()
Additional contact information
Shuhui Sun: Chinese Academy of Sciences
Jiaming Li: Chinese Academy of Sciences and China National Center for Bioinformation
Si Wang: Xuanwu Hospital Capital Medical University
Jingyi Li: Chinese Academy of Sciences
Jie Ren: Chinese Academy of Sciences
Zhaoshi Bao: Capital Medical University
Le Sun: Capital Medical University
Xibo Ma: Chinese Academy of Sciences
Fangshuo Zheng: The Fifth People’s Hospital of Chongqing
Shuai Ma: Chinese Academy of Sciences
Liang Sun: Aging Biomarker Consortium
Min Wang: Chinese Academy of Sciences
Yan Yu: Chinese Academy of Sciences
Miyang Ma: Chinese Academy of Sciences
Qiaoran Wang: Chinese Academy of Sciences and China National Center for Bioinformation
Zhiyuan Chen: Chinese Academy of Sciences
He Ma: Chinese Academy of Sciences
Xuebao Wang: Chinese Academy of Sciences
Zeming Wu: Chinese Academy of Sciences
Hui Zhang: Chinese Academy of Sciences
Kaowen Yan: Chinese Academy of Sciences
Yuanhan Yang: Chinese Academy of Sciences
Yixin Zhang: Chinese Academy of Sciences
Sheng Zhang: Chinese Academy of Sciences
Jinghui Lei: Xuanwu Hospital Capital Medical University
Zhao-Qian Teng: Chinese Academy of Sciences
Chang-Mei Liu: Chinese Academy of Sciences
Ge Bai: Zhejiang University School of Brain Science and Brain Medicine
Yan-Jiang Wang: Aging Biomarker Consortium
Jian Li: Aging Biomarker Consortium
Xiaoqun Wang: Capital Medical University
Guoguang Zhao: Xuanwu Hospital Capital Medical University
Tao Jiang: Capital Medical University
Juan Carlos Izpisua Belmonte: Altos Labs
Jing Qu: Chinese Academy of Sciences
Weiqi Zhang: Chinese Academy of Sciences
Guang-Hui Liu: Chinese Academy of Sciences

Nature, 2023, vol. 624, issue 7992, 611-620

Abstract: Abstract Ageing is a critical factor in spinal-cord-associated disorders1, yet the ageing-specific mechanisms underlying this relationship remain poorly understood. Here, to address this knowledge gap, we combined single-nucleus RNA-sequencing analysis with behavioural and neurophysiological analysis in non-human primates (NHPs). We identified motor neuron senescence and neuroinflammation with microglial hyperactivation as intertwined hallmarks of spinal cord ageing. As an underlying mechanism, we identified a neurotoxic microglial state demarcated by elevated expression of CHIT1 (a secreted mammalian chitinase) specific to the aged spinal cords in NHP and human biopsies. In the aged spinal cord, CHIT1-positive microglia preferentially localize around motor neurons, and they have the ability to trigger senescence, partly by activating SMAD signalling. We further validated the driving role of secreted CHIT1 on MN senescence using multimodal experiments both in vivo, using the NHP spinal cord as a model, and in vitro, using a sophisticated system modelling the human motor-neuron–microenvironment interplay. Moreover, we demonstrated that ascorbic acid, a geroprotective compound, counteracted the pro-senescent effect of CHIT1 and mitigated motor neuron senescence in aged monkeys. Our findings provide the single-cell resolution cellular and molecular landscape of the aged primate spinal cord and identify a new biomarker and intervention target for spinal cord degeneration.

Date: 2023
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DOI: 10.1038/s41586-023-06783-1

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