Transplantation of embryonic spinal cord-derived cells to prevent muscle atrophy after various peripheral nerve injuries

Abstract

Peripheral nerves are prone to traumatic injuries, leading to the loss of motor and sensory functions. Even though surgical repair is possible, the extent of functional recovery after the repair is determined by factors such as the site and type of injury sustained, the amount of time that has passed before the intervention, and the distance over which the axons must extend. After both spinal and severe nerve injury, the chronically denervated muscle tissue begins to atrophy and becomes less receptive to reinnervation, thereby reducing the possibility of full functional recovery. Therefore, other interventions, such as cell therapy, should be applied to keep the muscles in good condition. In the current study, cells were isolated from the E14.5 rat spinal cord and used directly as fetal cells or cultured to obtain a population of pure neural progenitor cells, and injected into the distal musculocutaneous nerve close to the muscle to allow the cells to reach the muscles rapidly and limit muscular atrophy. To investigate the intrinsic properties of the cells, they were isolated from 3 spinal cord segments separately and comparatively. The hypothesis was that grafted cells form connections with target muscle and restrict their atrophy, allowing a larger window of time for surgical repair. In the first study, abovementioned cells were used after musculocutaneous nerve transection in the absence of surgical repair. In this model, grafted cells were able to survive, extend their axons and reform the connections with target muscles that, in turn, showed reduced muscle atrophy. The functional viability of these new connections was further demonstrated by electromyographic measurements. Moreover, fetal spinal cord cells kept their neuronal identity in vivo, while derived progenitor cells had mostly differentiated into glial cells, also seen in vitro. Consequently, fetal cells enhanced the muscle condition more compared to neural progenitor cells. In the comparison of segment-specific cells, lumbar cells prevented slightly more muscle atrophy compared to the thoracic and cervical cells. Following this result, lumbar fetal cells were tested out on nerve injury models with 6-weeks delayed surgical repair that allowed the host axons to regenerate. In a temporary crush model, the cells were able to reduce muscle atrophy, resulting in an earlier and improved functional recovery after surgical repair. In contrast, when severe nerve transection with delayed end-to-end repair was used, cells formed a barrier against weak host regenerating axons, and therefore no beneficial effect on muscles was observed. In the second study, brachial plexus avulsion was followed by 2-weeks delayed ventral root reimplantation. Application of exogenous GDNF to injured spinal cord greatly prevented the motoneuron death and enhanced the regeneration and axonal sprouting, while lumbar fetal cell graft into the distal nerve reduced the muscle atrophy and enhanced the functional recovery. The combination of GDNF and cell graft reunited the positive effects on motoneuron survival and functional recovery and could be therefore considered as a promising strategy for this kind of injuries.