Single-cell RNA sequencing reveals time- and sex-specific responses of mouse spinal cord microglia to peripheral nerve injury and links ApoE to chronic pain

Shannon Tansley, Sonali Uttam, Alba Ureña Guzmán, Moein Yaqubi, Alain Pacis, Marc Parisien, Haley Deamond, Calvin Wong, Oded Rabau, Nicole Brown, Lisbet Haglund, Jean Ouellet, Carlo Santaguida, Alfredo Ribeiro-da-Silva, Soroush Tahmasebi, Masha Prager-Khoutorsky, Jiannis Ragoussis, Ji Zhang, Michael W. Salter, Luda Diatchenko, Luke M. Healy (), Jeffrey S. Mogil () and Arkady Khoutorsky ()
Additional contact information
Shannon Tansley: McGill University
Sonali Uttam: McGill University
Alba Ureña Guzmán: McGill University
Moein Yaqubi: McGill University
Alain Pacis: Canadian Centre for Computational Genomics, McGill Genome Centre
Marc Parisien: McGill University
Haley Deamond: McGill University
Calvin Wong: McGill University
Oded Rabau: McGill University
Nicole Brown: McGill University
Lisbet Haglund: McGill University
Jean Ouellet: McGill University
Carlo Santaguida: Montreal Neurological Institute, McGill University
Alfredo Ribeiro-da-Silva: McGill University
Soroush Tahmasebi: University of Illinois at Chicago
Masha Prager-Khoutorsky: McGill University
Jiannis Ragoussis: McGill University
Ji Zhang: McGill University
Michael W. Salter: University of Toronto
Luda Diatchenko: McGill University
Luke M. Healy: McGill University
Jeffrey S. Mogil: McGill University
Arkady Khoutorsky: McGill University

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract Activation of microglia in the spinal cord following peripheral nerve injury is critical for the development of long-lasting pain hypersensitivity. However, it remains unclear whether distinct microglia subpopulations or states contribute to different stages of pain development and maintenance. Using single-cell RNA-sequencing, we show that peripheral nerve injury induces the generation of a male-specific inflammatory microglia subtype, and demonstrate increased proliferation of microglia in male as compared to female mice. We also show time- and sex-specific transcriptional changes in different microglial subpopulations following peripheral nerve injury. Apolipoprotein E (Apoe) is the top upregulated gene in spinal cord microglia at chronic time points after peripheral nerve injury in mice. Furthermore, polymorphisms in the APOE gene in humans are associated with chronic pain. Single-cell RNA sequencing analysis of human spinal cord microglia reveals a subpopulation with a disease-related transcriptional signature. Our data provide a detailed analysis of transcriptional states of mouse and human spinal cord microglia, and identify a link between ApoE and chronic pain in humans.

Date: 2022
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DOI: 10.1038/s41467-022-28473-8

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