Time associated decline in neurotrophic properties of neural stem cell grafts render them dependent on brain region-specific environmental support

Abstract

Fetal neural stem/precursor cells (NPCs) possess powerful neurotrophic properties by which they can facilitate self repair processes in the adult central nervous system. The therapeutic value of NPC therapy in neurodegenerative diseases is critically dependent on their long term survival and enduring functional properties. An important aspect of NPC neurotrophic properties is their ability to support their own survival independent of any exogenous growth factor. Here, we examined whether NPCs survive and maintain their properties for extended periods of time, or become dependent on environmental support. Two months following transplantation to naïve brains, large grafts were detected in the ventricles and hippocampus, but only little survival was evident in the striatum. To point at possible regional characteristics which underlie the differential survival of NPC grafts we performed several manipulations of the brain environment. Acute neurotoxic injury with 6-hydroxydopamine induced a 3-fold increase in striatal graft survival, associated with induction of nestin, CD31, β1-integrin, GFAP and cycling cells. Disruption of the extracellular matrix structure of this reactive niche by continuous blockage of host striatum β1-integrin caused 73% reduction in graft survival. In the hippocampus, NPC graft survival did not correspond to β1-integrin and CD31 expression. This suggests that hippocampal environmental support to graft survival rely on different mechanisms than in the reactive striatum. In correlation with in vivo findings, long term cultured neural precursors exhibited an increase in apoptotic cells and dramatic decline in neurotrophic effects, as indicated by two in vitro functional assays. We conclude that long-term changes in transplanted NPC properties render them dependent on region specific environmental support. The major extracellular matrix protein β1-integrin is essential for providing tissue support for graft survival in the striatum. The neurotrophic properties of transplanted neural stem cells are limited in time, representing a shortcoming which should be taken into consideration when developing clinical transplantation protocols for chronic neurological disorders.