P2Y12-targeted modulation of microglial phenotypes: A novel therapeutic strategy for enhanced axonal regeneration
Kai Zhang1, Runlin Wen1, Wanrong Ma2
1Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China.
Aims:
Microglia activation after spinal cord injury (SCI) is a double-edged sword, modulation of the activated microglia populations toward pro-regenerative phenotypes highlights the potential therapeutic implications. P2Y12, a microglia-specific marker, remains underexplored in its capacity to polarize microglial activation populations in SCI repair. We aimed to explore the effects of modulating P2Y12 on microglia function after spinal cord injury, and further on axonal regeneration and motor recovery after spinal cord injury.
Materials And Methods:
The study employed both in vitro and in vivo models, using BV2 cells and a mouse model of SCI, respectively. Ticagrelor, a P2Y12 antagonist, was administered via a collagen scaffold to ensure stable and sustained release. Transcriptome sequencing analysis, immunofluorescence staining, and Basso Mouse Scale (BMS) scores were used to assess microglial activation, axonal regeneration, and functional recovery.
Key Findings:
Herein, we observed P2Y12+ microglia localized predominantly at the lesion periphery within 3 days post injury (dpi), manifesting a pro-inflammatory phenotype, but not anti-inflammatory phenotype. In vitro investigations revealed that P2Y12 inhibition of the activated microglia curtailed pro-inflammatory differentiation while augmenting anti-inflammatory differentiation.
Significance:
Leveraging this insight, we engineered a collagen scaffold-based delivery system for sustained release of the P2Y12 antagonist, ticagrelor, at the injury site in a mouse complete SCI model. Notably, P2Y12 suppression markedly enhanced axonal regeneration within the injured site and ameliorated lower limb motor functions in SCI mice. Collectively, our findings illuminate P2Y12-targeted microglial modulation as a promising therapeutic approach for SCI.
Insights
Targeting P2Y12 on microglia after spinal cord injury (SCI) promotes axonal regeneration and motor function recovery. Inhibiting P2Y12 shifts microglia to a pro-regenerative state, offering a new therapeutic strategy for SCI.
Area of Science:
- Neuroscience
- Immunology
- Regenerative Medicine
Background:
- Microglia activation after spinal cord injury (SCI) presents a dual role, with potential for therapeutic modulation toward pro-regenerative phenotypes.
- The microglia-specific marker P2Y12's role in polarizing microglial activation states post-SCI requires further investigation.
Purpose of the Study:
- To investigate the impact of modulating P2Y12 on microglia function following SCI.
- To assess the effects of P2Y12 modulation on axonal regeneration and motor recovery in SCI models.
Main Methods:
- Utilized in vitro (BV2 cells) and in vivo (mouse SCI model) approaches.
- Administered ticagrelor, a P2Y12 antagonist, via a sustained-release collagen scaffold.
- Employed transcriptome sequencing, immunofluorescence, and Basso Mouse Scale (BMS) for analysis.
Main Results:
- P2Y12-positive microglia at the SCI lesion periphery exhibited a pro-inflammatory phenotype.
- In vitro, P2Y12 inhibition reduced pro-inflammatory microglia differentiation and increased anti-inflammatory differentiation.
- Sustained ticagrelor release via scaffold enhanced axonal regeneration and improved motor function in SCI mice.
Conclusions:
- P2Y12-targeted microglial modulation, using sustained ticagrelor delivery, promotes axonal regeneration and motor recovery after SCI.
- This approach highlights P2Y12 suppression as a promising therapeutic avenue for spinal cord injury.
- The engineered collagen scaffold facilitates localized, sustained drug delivery for SCI treatment.
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