AbstractPeripheral sensory neurons regenerate their axons after injury to regain function, but this ability declines with age. The mechanisms behind this decline are not fully understood. While excessive production of endothelin 1 (ET-1), a potent vasoconstrictor, is linked to many diseases that increase with age, the role of ET-1 and its receptors in axon regeneration is unknown. Using a single cell RNAseq approach, we reveal that in dorsal root ganglia (DRG), satellite glial cells (SGCs), which completely envelop the sensory neuron soma, express the endothelin B receptor (ETBR), while ET-1 is expressed by endothelial cells. Inhibition of ETBRex-vivoin DRG explant cultures improves axon growth in both adult and aged conditions. In vivo,treatment with the FDA- approved compound, Bosentan, improves axon regeneration and reverses the age-dependent decrease in axonal regenerative capacity. Bosentan treatment also enhances the expression of connexin 43 in SGCs after injury in adult and aged mice. These results reveal that inhibiting ETBR function enhances axon regeneration and rescues the age-dependent decrease in axonal regenerative capacity, providing a potential avenue for future therapies.One Sentence SummaryInhibition of endothelin signaling improves nerve regeneration after central and peripheral injuries and counters age-related regenerative decline.
