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.
