Fyhn Cormier posted an update 1 month, 1 week ago
The inhibition is brought to effect via activation of the MEKERK pathway and blocking this pathway allows soluble NRG type II to promote myelination.The activation of MEKERK pathway is capable of inhibiting myelination alone as well as in cooperation with low levels of soluble NRG type II. Recovery from PNI is often suboptimal and lifelong functional impairment and neuropathic pain is common.Autologous nerve grafting has been the standard treatment in cases of severed nerve injuries that create a gap between the proximal and distal nerve.However, nerve grafting requires that a healthy nerve is harvested from the patient, which can itself lead to donorsite morbidity, including chronic and debilitating neuropathic pain.Moreover, nerve graft repair yields relatively poor results; only of patients recover full motor function and only regain full sensory function after median nerve repair.Much of this failure is due to poor engraftment between donor and recipient nerves and delayed surgical intervention, resulting in distal muscle atrophy and fibrosis.Schwann cells, which are required to support axonal regeneration during peripheral nerve repair, also have limited remyelination capacity in chronically denervated distal nerves. Given the inability of the peripheral nerve to selfheal or use therapeutic interventions to repair the injured nerve, there is a growing need to develop alternative therapeutic approaches.One alternative to autologous nerve grafting is the use of nerve conduits, also called axon guidance channels, in which axonal regeneration bridges the nerve ends within the lumen of the tube. Nerve graft materials used in nerve conduits are biocompatible, elicit no or negligible inflammatory response, promote axonal elongation and have an appropriate degradation rate after nerve regrowth.There are a few reports of successful nerve repair using standalone nerve conduits, but in humans, repair is typically limited to small digit nerves and outcomes are similar to nerve autografts.Nerve conduits also fare poorly compared to autografts when used in critical length defects, with the risk of complete regeneration failure owing to the lack of cellular support within the conduit.Schwann cells are able to promote axonal growth, in part, through the release of neurotrophic factors, making them an excellent supplement to conduits.Schwann cell dedifferentiation post injury is triggered by a loss of axonal contact.Peripheral nerve injury may result in axonal degeneration.Axonal and myelin debris is observed distal to the site of injury.Advanced age also greatly diminishes nerve regenerative capacity.Interestingly, there are sexually dimorphic differences in nerve repair with the female cohort exhibiting faster regeneration post injury compared to males. However, further studies are required to identify the molecular network governing these differences.However, there are also potential issues with directed differentiation strategies that must be considered.In general, cellular reprogramming is achieved by the overexpression of lineagespecifying transcription factors andor by the addition of extrinsic factors such as growth factors or small molecule antagonists or agonists, which specify alternative cell identities, repress the identity of the starting cell type, and remove epigenetic barriers to alter cell state. However, the need to transit through a pluripotent stem cell state poses several problems, including the possibility of generating partially reprogrammed cells that may proliferate andor differentiate erroneously.