PDGFRα-Positive B Cells Are Neural Stem Cells in the Adult SVZ that Form Glioma-like Growths in Response to Increased PDGF Signaling

Abstract

Neurons and oligodendrocytes are produced in the adult brain subventricular zone (SVZ) from neural stem cells (B cells), which express GFAP and have morphological properties of astrocytes. We report here on the identification B cells expressing the PDGFRalpha in the adult SVZ. Specifically labeled PDGFRalpha expressing B cells in vivo generate neurons and oligodendrocytes. Conditional ablation of PDGFRalpha in a subpopulation of postnatal stem cells showed that this receptor is required for oligodendrogenesis, but not neurogenesis. Infusion of PDGF alone was sufficient to arrest neuroblast production and induce SVZ B cell proliferation contributing to the generation of large hyperplasias with some features of gliomas. The work demonstrates that PDGFRalpha signaling occurs early in the adult stem cell lineage and may help regulate the balance between oligodendrocyte and neuron production. Excessive PDGF activation in the SVZ in stem cells is sufficient to induce hallmarks associated with early stages of tumor formation.

Identification of OLIG2 as the most specific glioblastoma stem cell marker starting from comparative analysis of data from similar DNA chip microarray platforms

“…First, a subpopulation of type B and type C cells in the adult rodent brain express Olig2 [61,70,71]. Second, exposure to glioma-relevant mitogens, such as EGF or PDGF, stimulates proliferation of Olig2+ rapidly dividing "type C" transit amplifying cells and glioma-like growths [72]. Moreover, all gliomas, irrespective of grade, express Olig2 in at least some fraction of the malignant cell population [42,[73][74][75][76][77][78].…”

The microenvironment of the embryonic neural stem cell: Lessons from adult niches?

“…SEZ stem cells also express the PDGF␣ receptor and the level of expression maintains the balance between neuron and oligodendrocyte production. Conditional ablation of the receptor in SEZ stem cells results in an arrest in oligodendrogenesis but not neurogenesis while infusion of PDGF␣ into the lateral ventricles increased B cell production and stopped neuroblast generation (Jackson et al, 2006).…”

Epigenetic regulation of aging stem cells

“…In other hematopoietic malignancies, an initiating lesion in self-renewing stem cells may progress to malignancy when coupled with increased mutagenic events in the more rapidly expanding progenitor pool (Bonnet and Dick 1997;Cozzio et al, 2003;Rossi et al, 2008). Similarly, adult SVZ NSCs have been proposed as the origin of gliomas and astrocytomas (Lewis 1968;Vick et al, 1977;Holland et al, 2000;Sanai et al, 2005;Zhu et al, 2005;Jackson et al, 2006). Brain tumor cells share both anatomical location with SVZ niches and similar properties, including dependence on signaling pathways regulating normal NSC self-renewal Lim et al, 2007).…”