Manipulating neural-stem-cell mobilization and migration in vitro

Neural stem-cell transplantation is a promising strategy for the treatment of neural diseases and injuries, since the central nervous system (CNS) has a very limited capacity to repopulate the lost cells. Transplantation strategies face many difficulties including low viability, lack of control of stem-cell fate, and low levels of cell engraftment after transplantation. An alternative strategy for CNS repair without transplantation is using endogenous neural stem cells (NSCs) and precursor cells. Hepatocyte growth factor (HGF), a pleiotropic cytokine of mesenchymal origin, exerts a strong chemoattractive effect on stem cells. Leukemia inhibitory factor (LIF), a key regulator for stem-cell proliferation, mobilization, and fate choices, is currently being characterized for endogenous NSC manipulation for brain regeneration. In this study, HGF and LIF have been loaded into hydrogels and degradable nanoparticles, respectively, for sustained, long-term, localized delivery. We examine the use of HGF-loaded hydrogels and LIF-loaded nanoparticles for manipulating migration and mobilization of human NSCs in vitro. The combination of LIF-loaded nanoparticles and HGF-loaded hydrogels significantly mobilized hNSCs and promoted their migration in vitro. Studies are in progress to evaluate endogenous NSC mobilization and migration in vivo with simultaneous, controlled delivery of LIF at the natural reservoir of endogenous NSCs and HGF at the injury or disease site for in situ tissue regeneration.