Repopulated spinal cord microglia exhibit a unique transcriptome and contribute to pain resolution

Cell Reports, 2024 · DOI: 10.1016/j.celrep.2024.113683 · Published: February 27, 2024

Simple Explanation

Microglia, immune cells in the spinal cord, have been thought to worsen pain. This study found that when microglia are temporarily removed and then return (repopulated), pain actually decreases. The returning microglia are different from the original ones and have unique genes turned on. Researchers compared genes in these repopulated microglia in mice to genes found in human spinal cord microglia. This helped identify specific human genes that might be targets for new pain treatments. This research offers clues for creating drugs that target microglia to resolve pain after an injury.

Study Duration

9 Weeks

Participants

Adult male and female mice

Evidence Level

Not specified

Key Findings

1
Microglia depletion and repopulation at the acute-to-chronic transition completely resolved pain and improved peripheral inflammation.
2
Repopulated microglia are morphologically and transcriptomically distinct from control microglia.
3
Targets with human relevance were identified by overlapping mouse genes of interest with a human spinal cord single-nucleus microglia transcriptome dataset.

Research Summary

Microglia are implicated as primarily detrimental in pain models; however, they exist across a continuum of states that contribute to homeostasis or pathology depending on timing and context. Unexpectedly, we observe complete resolution of pain coinciding with microglial repopulation rather than depletion. This work presents a comprehensive approach to gene discovery in pain and provides datasets for the development of future microglial-targeted therapeutics.

Practical Implications

Drug Development

Identified human-relevant microglia genes can be targeted for analgesic drug development.

Therapeutic Timing

Timing of microglial modulation is crucial; repopulation, not just depletion, can resolve pain.

Personalized Medicine

Sex-specific microglial signatures suggest potential for personalized pain therapies.

Study Limitations

1
Lack of further confirmation of identified microglial pro-resolution genes as contributors to pain.
2
Isolation of microglia for sequencing from whole lumbar spinal cord, not only the injured dorsal horn.
3
Limited human samples for confirmation of microglial genes; only one male and one female sample were used.

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