REDIRECTION OF DOUBLECORTIN-POSITIVE CELL MIGRATION BY OVER-EXPRESSION OF THE CHEMOKINES MCP-1, MIP-1alpha AND GRO-alpha IN THE ADULT RAT BRAIN

摘要

Inflammation-induced chemoattraction plays a major role in adult subventricular zone (SVZ)-derived precursor cell migration following neural cell loss, in particular through the release of chemokines by activated microglia and macrophages. We previously demonstrated that mono-cyte chemotactic protein-1 (MCP-1) (chemokine (c-c motif) ligand (CCL)2), macrophage inflammatory protein-1 alpha (MIP-1alpha) (CCL3) and growth regulatory protein-alphaa (GRO-alpha) (chemokine (c-x-c motif) ligand (CXCL)1) are up-regulated following neural cell loss in the adult striatum and act as potent chemoattractants for SVZ-derived precursor cells in vitro. Based on these observations, the current study aimed to examine the individual effect of MCP-1, MIP-1alpha and GRO-alpha on the migration of adult SVZ-derived neural precursor cells in vivo. To address this without the confounding effects of injury-induced chemotactic cues, adeno-associated viral (AAV)_2-mediated in vivo gene transfer was used to ectopically express either MCP-1, MIP-1alpha or GRO-alpha, or the control red fluorescent protein (RFP) in the normal adult rat striatum. The extent of doublecortin (Dcx)-positive cell recruitment from the SVZ into the striatal parenchyma was then determined at 4 and 8 weeks following AAV_2 injection. Ectopic expression either of MCP-1 or MIP-1alpha in the normal adult rat brain significantly increased the number of Dcx-positive cells and the extent of their migration into the striatum at both 4 and 8 weeks after vector injection but did not promote either precursor cell proliferation or neural differentiation. In contrast, while over-expression of GRO-alpha 4 weeks after vector injection induced a significant increase in Dcx-positive cell migration compared to control, this effect was reduced to control levels by 8 weeks post injection. Further, direct comparison between MCP-1, MIP-1alpha and GRO-alpha at both 4 and 8 weeks post vector injection indicated that GRO-alpha may have a reduced effect in inducing Dcx-positive cell migration when compared to MCP-1. Combined, these results confirm that over-expression of the chemokines MCP-1, MIP-1alpha and GRO-alpha can override cues directing precursor cell migration along the rostral migratory stream (RMS) and provides a mechanism by which neural precursor cell migration can be redirected into a non-neurogenic region. Differences in the migratory effect observed between individual chemokine may be due to ligand-binding affinity and/or receptor expression on SVZ-derived precursor cells.