RPS3-Enriched Extracellular Vesicles Mediate Liver-Spinal Cord Inter-Organ Communication.

Area of Science:

• Neuroscience
• Cell Biology
• Immunology

Background:

• Spinal cord injury (SCI) disrupts inter-organ communication, impacting endogenous repair mechanisms.
• Extracellular vesicles (EVs) mediate communication between the spinal cord and peripheral organs following injury.

Purpose of the Study:

• To identify peripheral organs and specific molecules involved in inhibiting neuronal repair after SCI.
• To elucidate the mechanism by which liver-derived EVs affect neural stem cells (NSCs) and astrocytes.

Main Methods:

• Proteomic analysis of plasma EVs from SCI patients and RNA sequencing of post-injury livers.
• Characterization of liver-derived EVs (LEVs) and their uptake by neural cells.
• Investigation of the role of ribosomal protein S3 (RPS3) and NF-κB signaling.
• In vivo studies involving Kupffer cell (KC) depletion and hepatic RPS3 inhibition.

Main Results:

• Increased RPS3 in plasma EVs and LEVs post-SCI, with LEVs targeting spinal cord lesions.
• RPS3 activates NF-κB signaling in NSCs and astrocytes, inhibiting differentiation and promoting neuroinflammation.
• Activated KCs are the primary source of RPS3, amplifying its hepatic production.
• Depleting KCs or hepatic RPS3 restored axonal regeneration, remyelination, and neurological function.

Conclusions:

• A liver-spinal cord axis exists where RPS3-enriched hepatic EVs inhibit CNS regeneration via NF-κB activation.
• RPS3 represents a potential prognostic biomarker for SCI.
• Targeting hepatic RPS3 and KCs offers a novel therapeutic strategy for SCI recovery.