The peripheral nervous system is capable of regeneration, albeit not as much as desired. Lasting loss of function following injury is certainly possible, particularly following injury to larger nerves. The research community has long been interested in finding ways to improve this situation, some of which might be applicable to the much less regenerative central nervous system as well. Peripheral nerves are made up of bundled axons, long connections between neurons that pass signals back and forth. It is the regeneration of these axons that is the primary concern. Peripheral nervous system axons can be as much as several feet long, but even these are capable of regeneration and regrowth - at least until old age dismantles this ability along with many others.
In today's open access paper, researchers uncover an approach to improving peripheral axon regeneration that works in both young and old tissues. This appears to function at least in part by changing the behavior of the satellite glial cells that surround peripheral neurons making up nerve ganglia. The function of these glial cells is not completely understood, and therefore how this approach functions in detail is not completely understood. At the high level, it seems likely that (a) satellite glial cells regulate the environment of the ganglia in ways that are conducive to normal function, analogous to the supporting role of glial cells in the brain, (b) their ability to do this declines with age, and © there are ways to favorably change the behavior of satellite glial cells that have few negative consequences. The small molecule drug used in this study may or may not count as one of those ways, but more targeted approaches can be envisaged.
Endothelin B receptor inhibition rescues aging-dependent neuronal regenerative decline
Peripheral 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 single-cell RNA sequencing, we show that satellite glial cells (SGCs), which completely envelop the sensory neuron cell body residing in the dorsal root ganglia (DRG), express the endothelin B receptor (ETBR), while ET-1 is expressed by endothelial cells. Inhibition of ETBR ex vivo in DRG explant cultures improves axon growth in both adult and aged conditions.
In vivo, treatment with the FDA-approved compound, Bosentan, a ETBR/ETAR antagonist used to treat pulmonary hypertension, improves axon regeneration and reverses the age-dependent decrease in axonal regenerative capacity. Single-nuclei RNA sequencing and electron microscopy analyses reveal a decreased abundance of SGCs in aged mice compared to adult mice. Additionally, the decreased expression of connexin 43 (Cx43) in SGCs in aged mice after nerve injury is partially rescued by Bosentan treatment.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.
View the full article at FightAging
