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.
Highlights
Activation of microglia in the spinal cord following peripheral nerve injury is critical for the development of long-lasting pain hypersensitivity
To reveal the heterogeneity of microglia at the singlecell level in the development and maintenance of chronic pain, we studied microglia in the spinal cord of mice subjected to the spared nerve injury (SNI) assay of neuropathic pain[22,23] (Fig. 1a)
Single-cell transcriptional analyses revealed that mouse and human spinal cord microglia exist in numerous heterogeneous subpopulations
Summary
Activation of microglia in the spinal cord following peripheral nerve injury is critical for the development of long-lasting pain hypersensitivity It remains unclear whether distinct microglia subpopulations or states contribute to different stages of pain development and maintenance. Single-cell RNA sequencing analysis of human spinal cord microglia reveals a subpopulation with a diseaserelated 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. We used single-cell RNA sequencing (scRNA-seq) to define transcriptional states of spinal cord microglia in mouse and human. Our studies identify the dynamic response of microglia to peripheral nerve injury in mice, link ApoE to chronic pain in mice and humans, and provide the single-cell characterization of human spinal cord microglia
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