Acid‑sensing ion channel‑1 contributes to the failure of myelin sheath regeneration following spinal cord injury by transcellular delivery of PGE2

Cellular & Molecular Biology Letters, 2024 · DOI: https://doi.org/10.1186/s11658-024-00672-9 · Published: November 20, 2024

Spinal Cord Injury Neurology Genetics

Simple Explanation

Traumatic spinal cord injuries (SCI) can lead to motor, sensory, and autonomic dysfunctions. The accumulation of inhibitory compounds in the injured area prevents axon regeneration and remyelination. Acid-sensing ion channel-1 (ASIC1A) is activated after SCI, but its role isn't clear. This study found that after SCI, ASIC1A prevents neural stem cells (NSCs) from turning into oligodendrocytes. This occurs because ASIC1A increases the production of prostaglandin E2 (PGE2) which is then released in extracellular vesicles (EVs). By inhibiting ASIC1A, researchers were able to promote myelin sheath regeneration and axonal remyelination. This suggests that blocking ASIC1A could be a potential treatment for SCI.

Study Duration

Not specified

Participants

SD rats, C57BL/6 mice, Asic1a-knockout (KO) mice

Evidence Level

Not specified

Key Findings

1
ASIC1A is upregulated in NSCs following spinal cord injury.
2
Acidic conditions activate ASIC1A, preventing NSCs from differentiating into oligodendrocytes.
3
ASIC1A upregulates PTGS2 in acid-treated NSCs and SCI rats, leading to increased PGE2 production and release via extracellular vesicles.

Research Summary

This study investigates the role of ASIC1A in spinal cord injury (SCI). It reveals that ASIC1A activation in neural stem cells (NSCs) prevents their differentiation into oligodendrocytes, hindering myelin sheath regeneration and axonal remyelination. The mechanism involves ASIC1A upregulating PTGS2, leading to increased production and release of PGE2 within extracellular vesicles (EVs). The transcellular NSC-to-NSC delivery of PGE2 inhibits NSC differentiation. Inhibition of ASIC1A, either pharmacologically or genetically, promotes myelin sheath regeneration and axonal remyelination, suggesting a promising therapeutic strategy for SCI.

Practical Implications

Therapeutic Target

Inhibition of ASIC1A presents a promising therapeutic strategy for enhancing myelin sheath regeneration and promoting axonal remyelination following SCI.

Understanding SCI Pathology

Elucidating the ASIC1A/PTGS2/PGE2 signaling axis provides insights into the mechanisms underlying the failure of myelin sheath regeneration after SCI.

Extracellular Vesicle Role

Highlighting the role of EVs in mediating the transcellular delivery of PGE2 underscores the importance of intercellular communication in SCI pathology.

Study Limitations

1
The study primarily used female animals to create a severe crush SCI model, limiting the generalizability of the findings to both sexes.
2
The study did not fully explore the impact of gender differences on the expression of ASIC1A and ASIC1A-related PTGS2.
3
The impact of gender differences on the effects of ASIC1A blockers in enhancing neurological recovery remains unclear.

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