Complementary patterns of gene expression by human oligodendrocyte progenitors and their environment predict determinants of progenitor maintenance and differentiation

Objective: Glial progenitor cells are abundant in adult human white matter. This study was designed to identify signaling pathways regulating their self-renewal and fate. Methods: We compared the transcriptional profiles of freshly sorted adult human white matter progenitor cells (WMPCs), purified by A2B5-based immunomagnetic sorting, with those of the white matter from which they derived. Results: We identified 132 genes differentially expressed by WMPCs; these included principal components of five receptordefined signaling pathways, represented by platelet derived growth factor receptor alpha (PDGFRA) and type 3 fibroblast growth factor receptor (FGFR3), receptor tyrosine phosphatase-/ (RTPZ), notch, and syndecan3. WMPCs also differentially expressed the bone morphogenetic protein 4 (BMP4) inhibitors neuralin and BAMBI (BMP and activin membrane-bound inhibitor), suggesting tonic defense against BMP signaling. Differential overexpression of RTPZ was accompanied by that of its modulators pleiotrophin, NrCAM, tenascin, and the chondroitin sulfate proteoglycans, suggesting the importance of RTPZ signaling to WMPCs. When exposed to the RTPZ inhibitor bpV(phen), or lentiviral-shRNAi against RTPZ, WMPCs differentiated as oligodendrocytes. Conversely, when neuralin and BAMBI were antagonized by BMP4, astrocytic differentiation was induced, which was reversible by noggin. Interpretation: The RTPZ and BMP pathways regulate the self-maintenance of adult human WMPCs, and can be modulated to induce their oligodendrocytic or astrocytic differentiation. As such, they provide targets by which to productively mobilize resident progenitor cells of the adult human brain. Ann Neurol 2006;59:763–779