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

ABSTRACT: 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 receptor-defined signaling pathways, represented by platelet derived growth factor receptor alpha (PDGFRA) and type 3 fibroblast growth factor receptor (FGFR3), receptor tyrosine phosphatase-beta/zeta (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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE26535 | GEO | 2011/02/01

SECONDARY ACCESSION(S): PRJNA136657

REPOSITORIES: GEO

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Project description:Adult neural progenitor cells (aNPCs) are a potential autologous cell source for cell replacement in neurologic diseases such as Parkinsonâs disease or stroke or for cell-based gene therapy for neurometabolic diseases. Easy accessibility, long-term expandability and detailed characterization of NPC properties are important requisites for their future translational/clinical applications. aNPC can be isolated from different regions of the adult human brain including the accessible subcortical white matter (aNPCWM), but systematic studies comparing long-term expanded aNPCWM with aNPC from neurogenic brain regions to check for their NPC characteristics and performance are not available. Freshly isolated cells from subcortical white matter and hippocampus (aNPCHIP) expressed oligodendrocyte progenitor cell (OPC) markers such as A2B5, NG2 and OLIG2 in ~20% of cells but no neural stem cell (NSC) markers such CD133 (Prominin1), NESTIN, SOX2 or PAX6. The EGF receptor (EGFR) protein was expressed in 18% of aNPCWM and 7% of aNPCHIP, but only a small fraction of 1 cell out 694 cells from white matter and only 1 out of 1,331 hippocampal cells were able to generate neurospheres. Studies comparing subcortical aNPCWM with their hippocampal counterparts showed that both NPC types expressed mainly markers of glial origin such as NG2, A2B5 and OLIG2, and the NSC/NPC marker Nestin, but no pericyte markers. Both NPC types were able to produce fully mature neurons, astrocytes and oligodendrocytes in comparable amounts to fetal NSC. Whole transcriptome analyses finally confirmed the strong similarity of aNPCWM with aNPCHIP. Our data show that aNPCWM are multipotent NPC with long-term expandability capacity similar to NPC from hippocampus making them an easily accessible source for possible autologous NPC-based treatment strategies. Isolation and propagation of multipotent NPCs. Adult human hippocampal (hip) and subcortical white matter (wm) tissue was obtained from routine epilepsy surgery procedures following informed consent of the subjects. All procedures were in accordance with the Helsinki convention and approved by the Ethical Committee of the University of Dresden (No. 47032006). All subjects underwent high-resolution magnetic resonance imaging excluding tumors and were screened for the presence of infectious disease. In all cases the neuropathological examinations did not reveal evidences for tumor formation. Gene expression Single-channel oligonucleotide microarray analysis. For the gene expression microarray analysis we used the Affimetrix U133A chips containing 22.215 probe sets representing at least 12.905 individual genes. The whole procedure was performed following the manufacturerâs standard protocol (Affimetrix, Santa Clara, CA). For the data processing, normalization was calculated with the GCRMA (GC content corrected Robust Multi-array Analysis) algorithm. fNSC: Human fetal neural stem cells, 2 biological rep aNPChip: Human adult neural progenitor cells isolated from hippocampus, 3 biological rep aNPCwm: Human adult neural progenitor cells isolated from white matter, 2 biological rep

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

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