Derived motor neurons transplantation promotes nerve regeneration in a rodent model of a chronically denervated nerve through delayed adoption of a chronic denervation phenotype

After acute injury, the peripheral nervous system regenerates more efficiently than the central nervous system, but this advantage is not maintained with chronic injuries. In large animals like humans, the slow rate of axon growth and the long distance between the central nervous system and end organ result in the adoption of a chronically denervated nerve phenotype even in the setting of acute injury: distal areas of the nerve become unable to support regenerating axons, even as the proximal aspect of the acute injury may be appropriately supportive of regeneration. We hypothesized that motor neuron transplantation into the denervated distal stump would maintain the regenerative capacity by effectively reducing the time and distance necessary for regeneration through relay formation as well as by supporting the host Schwann cells responsible for guiding regenerating axons. Using an in vitro assays, we showed the feasibility of relay formation by demonstrating ventral horn to derived-motor neuron synaptogenesis as identified by calcium imaging. Pilot studies of transplantation of embryonic stem cell-derived mouse motor neurons into chronically denervated rat nerves demonstrated improved regenerative capacity in the chronically denervated nerve following a delayed repair paradigm. While host to graft synaptogenesis was not observed, the Schwann cells in the transplanted nerve stump were maintained in a pro-regenerative state despite chronic denervation. These pilot data suggest cell transplantation can delay the adoption of a chronically denervated phenotype primarily by maintaining Schwann cells in a pro-regenerative state.