Generation of functional neural progenitors for spinal cord transplantation

Sammanfattning: Dorsal root avulsion injuries result in permanent impairment of sensory functions due to the disconnection of the peripheral nervous system from the spinal cord. Strategies aiming for the functional reconnection of sensory neurons with their targets in the spinal cord dorsal horn need to overcome the axonal growth non-permissive glial scar and provide a growth promoting environment. Stem cell therapy holds great promise in the context of root avulsion injuries as it combines the potential to provide a permissive and axonal growth attractive environment and the ability to form a neuronal relay between sensory neurons and spinal cord targets. In the first study, we show that human embryonic stem cell derived spinal cord neural progenitors(hNPs) restore sensorimotor functions in a model of dorsal root avulsion injury. The observed recovery of sensory functions was mediated by hNP cells forming growth permissive gates inthe glial scar that allowed spinal ingrowth of regenerating sensory axons. In the second study,we show that also human spinal cord neural stem/progenitor cells (hscNSPC) promote sensory axon ingrowth by the formation of a growth permissive tissue bridge that interferes with the spinal cord glial scar. Further, we tested whether this effect can be enhanced by combinatorial application of growth factors peptide mimetics. Interestingly, both hscNSPC and growth factor peptide mimetics alone but not in combination promote sensory regeneration. The observed failure of regeneration is likely caused by the reduced migration of hscNSPC when transplanted together with growth factor mimetics resulting in their inability to provide a continuous tissuebridge into the spinal cord. In the last study, we show first approaches to provide molecular tools that allow testing functional integration of stem cell derived neurons into the spinal cord.These tools are a prerequisite to test whether stem cells can also act as neuronal relays in the observed sensory regeneration events. In conclusion, this thesis provides first evidence that sensory regeneration is possible after dorsal root avulsion injury. This can be achieved by transplantation of human stem cell derived neuronal cells and to a certain degree by growth factor peptide mimetics.