Towards the Replacement Therapy Using Neural Stem/Progenitor cells for Neurological Disorders: Strategies to Enhance Therapeutic Capacity of Transplantation Approaches

Abstract

Transplantation of neural stem/progenitor cells (NPC) holds potential to improve functional outcomes in various neurological disorders. It seems more difficult than previously envisioned, however, to functionally replace the lost neural cells by grafted NPCs. A lack of appropriate developmental cues in the injured tissue contributes to the failure to guide the NPCs to survive, differentiate, grow axons, and functionally integrate to the host neural circuit. Therefore, we need to design possible strategies to recapitulate the developmental processes for the grafted NPCs to fully mature into functional neural cells. To enhance survival of NPCs following transplantation, pharmacological treatments targeting apoptosis and inflammation can be combined with transplantation. Genetic overexpression of prosurvival genes or growth factors can also improve survival. In vitro predifferentiation not only provides neural cells of a specific lineage in high purity but also greatly reduces chances of a tumor formation. Genetic overexpression of various transcription factors or manipulating molecular microenvironment of the host can also be tried to force differentiation of NPCs to a desired lineage. Pharmacological application to overcome myelin inhibition or enzymatic degradation of the inhibitory extracellular matrix will enhance axonal growth of NPC-derived neurons. Increasing synaptic activity by behavioral training or patterned electrical stimulation may promote proper development of synaptic integration and myelination of the axon. A thorough understanding of cellular and molecular aspects of neural development will help design more sophisticated strategies to enhance therapeutic capacity of NPC transplantation to reconstruct the damaged neural circuit.