Elevated ESM1 facilitates peripheral nerve regeneration via enhancing Schwann cell activity and developing a pro-regenerative microenvironment

Nerve injury often results in restricted regenerative capacity, leading to long-term functional disability. Growth factors are essential mediators of tissue repair and hold therapeutic promise for enhancing nerve regeneration. Identifying differentially expressed growth factors in injured nerves may reveal key promoters of nerve regeneration. In this study, through transcriptomic profiling of injured sciatic nerves in young and aged rats, we revealed dynamic dysregulation of growth factors, and identified endothelial cell-specific molecule 1 (ESM1) as an up-regulated growth factor following injury. Recombinant ESM1 protein enhanced Schwann cell viability, proliferation, and migration both in vitro and in vivo. Furthermore, the administration of ESM1 supports angiogenesis, reduces apoptosis, and accelerates axon regeneration in the injury site. Mechanistically, ESM1 elevated phosphorylated MEK1/2 and ERK1/2 levels and hence established a regenerative-permissive microenvironment. Our findings reveal the beneficial role of ESM1 in nerve regeneration and hence underscore its potential as a promising therapeutic avenue for peripheral nerve injury.