Proteolipid Protein 1 Homeostatically Regulates Schwann and Endothelial Cell Function and Communication in Peripheral Nerve Repair.

The interplay between Schwann cells (SCs) and vascular endothelial cells (ECs) is widely acknowledged as a crucial determinant of successful peripheral nerve regeneration, yet the key molecular mediators that orchestrate this crosstalk remain poorly defined and mechanistically elusive. This study aims to identify novel regulators of Schwann cell-endothelial cell communication and their functional impact on regeneration. Using in vitro co-culture models, live-cell imaging, and transcriptomic sequencing, cell interactions were characterized and the top candidate gene, proteolipid protein 1 (Plp1), was identified. Dynamic, directed communication was observed primarily via Schwann cell-derived extracellular vesicles (EVs), and it was confirmed that PLP1 is packaged into EVs and internalized by recipient ECs. Functionally, Plp1 overexpression in ECs inhibited their proliferation, migration, and tube formation. Meanwhile, Plp1 knockdown in SCs enhanced proliferation and migration but impaired their differentiation. In a rat model of sciatic nerve injury, Plp1 knockdown promoted early angiogenesis but disrupted vascular orientation and myelin compaction. Collectively, this study identifies PLP1 as a novel homeostatic regulator in peripheral nerve regeneration that modulates both SC function and EC behavior while also participating in EV-mediated intercellular communication, thereby uncovering its novel biological roles beyond its well-characterized function as a structural myelin component.