The potential role of chemokines in redirecting progenitor cell migration into the lesioned striatum

Abstract

A number of studies have demonstrated directed migration of neural progenitor cells to sites of brain injury and disease. However, a detailed examination of when a cell is “born” in relation to injury induction and the migratory response of that cell has not previously been determined. This study therefore examined the temporal correlation between progenitor cell proliferation (“birth”) and neuroblast migratory response into the damaged striatum following quinolinic acid (QA) lesioning of the adult rat striatum. Retroviral labeling of subventricular zone (SVZ)–derived progenitor cells demonstrated that cell loss in the QA-lesioned striatum increased progenitor cell migration through the rostral migratory stream for up to 30 days. In addition, a population of dividing cells originating from the SVZ generated doublecortin positive neuroblasts that migrated into the damaged striatum in response to cell loss invoked by the QA lesion. The majority of doublecortin positive neuroblasts present in the damaged striatum were generated from progenitor cells dividing within two days prior to, or on the day of QA lesioning. In contrast, cells dividing two or more days following QA lesioning, migrated into the striatum and exhibited a glial phenotype. These results demonstrate that directed migration of SVZ-derived cells and neuroblast differentiation in response to QA lesioning of the striatum is acute and transient. We subsequently demonstrated a role for the chemokines MCP-1, MIP-1α and GRO-α in directing adult SVZ-derived progenitor cell migration following striatal cell death. MCP-1, MIP-1α and GRO-α were significantly upregulated in the striatum 2-3 days following QA-induced lesioning, correlating with maximum SVZ-derived progenitor cell recruitment into the lesioned striatum. We established that SVZ-derived progenitor cells express receptors for each chemokine, and demonstrated MCP-1, MIP-1α and GRO-α to be potent chemoattractants for SVZ-derived progenitor cells in vitro. Immunofluorescence revealed MCP-1, MIP-1α and GRO-α are predominantly expressed in the striatum by NG2-positive cells that appear to infiltrate from the bloodstream 6 hours following QA lesioning. These results indicate that upregulation of MCP-1, MIP-1α, GRO-α following striatal cell death leads to chemoattraction of SVZ-derived progenitor cells into the damaged striatum and raises a potential role for blood-derived cells in directing the recruitment of SVZ progenitor cells following brain injury.