The remarkable plasticity of Schwann cells (SCs) enables these cells to mount a strikingly adaptive response to nerve injury and to promote axonal regeneration. In peripheral nerves SCs adopt the Remak (non-myelin) and myelin phenotypes which surrounds small and large diameter axons, respectively. After nerve injury both types of SCs convert to a repair-promoting phenotype activating a sequence of supportive functions that engineer myelin clearance, prevent neuronal death, and help axon growth and guidance (for a review see Jessen and Mirsky, 2019).
Unfortunately, in humans the clinical outcome after nerve injury is generally poor. Fading of the SC repair phenotype occurs in chronic denervation and is amplified in aging.
Our previous data indicate that SCs challenged with thrombin in the nanomolar range show an enhancement of their pro-regenerative potentials acting through its main receptor PAR1 (Pompili et al., 2017). A dramatic increase in thrombin activity can indeed be measured after nerve injury (Gera et al., 2016). While at low concentrations thrombin acts through its main receptor PAR1, at higher levels it can possibly activate other members of the PAR family that is PAR2, 3 and 4.
The aim of the present project is to analyze if and how the activation/inhibition of the different PARs modifies the SCs regenerative potential after nerve injury. In organotypic model system and SC primary cultures from rat/mouse sciatic nerve we will analyze if the activation/inhibition of the different members of the PAR family could potentiate the regenerative potentials of repair SCs. The expression of PARs will be also analyzed by immunofluorescence/confocal microscopy in human samples obtained from injured and uninjured nerves.
There are currently no therapies to effectively promote myelin regeneration after injury of the peripheral nervous system (PNS) and thus there is a great need to identify druggable target proteins that are potential regulators of PNS regeneration.
The striking regenerative potentials of peripheral nerves can be limited in humans by several factors such as aging and chronic denervation. Transected nerve stumps lose the capacity for supporting regeneration after about one month from injury.
There are currently no therapies to effectively protect myelin, or to promote myelin regeneration after injury of peripheral nerves. Thus, there is a great need to identify druggable target proteins that are integral regulators governing myelin production.
Since in the central nervous system PARs are key elements in governing myelin maintenance, our project has great potentials since at present, with the exception of PAR1, no data are available concerning the expression, location and function of the other members of the PAR family in peripheral nerves.
Future studies are needed to determine if and how PARs may be therapeutically targeted to prevent demyelination and promote remyelination in cases of injury or disease of the peripheral nervous system.
The comprehension of neuronal-glial interactions is fundamental for the study of the
pathophysiological conditions affecting peripheral nerves. In particular, non-myelin Schwann cell dysfunction could be responsible of some clinical peripheral neuropathies characterized by abnormal pain sensitivity