Chemokine CXCL1 is abundantly present in proliferative zones during brain development and in regions of remyelination, suggesting that it influences development of oligodendrocyte progenitors (OPC) in these regions. We studied in vitro the effects and possible mechanisms by which CXCL1 acts on human fetal OPC. In organotypic slice cultures of human fetal cortical ventricular/subventricular (VZ/SVZ) zones, blocking of CXCL1 signaling reduced significantly the proliferation of OPC. Moreover, exogenously added CXCL1 induced increase of OPC proliferation. Treatments of purified OPC cultures and cell depletion experiments demonstrated that this effect of CXCL1 was mainly indirect, mediated through astrocytes. We identified that CXCL1 acted through the extracellular signal regulated kinase (ERK1/2) pathway, activated primarily in astrocytes. In vitro, astrocytes stimulated with CXCL1 released several cytokines, but only the release of interleukin-6 (IL-6) was completely blocked by inhibition of ERK1/2 pathway. When released IL-6 was neutralized in slices, a decrease in OPC proliferation was demonstrated, while addition of IL-6 was able to return OPC proliferation in astrocyte-depleted slices to the control level. These results suggest that in the human fetal brain CXCL1 promotes proliferation of early OPC, acting in part through an ERK1/2-dependent pathway and release of IL-6 from astrocytes. © 2007 Wiley-Liss, Inc.