Glial progenitors in the brainstem give rise to malignant gliomas by platelet-derived growth factor stimulation

Abstract

Glial progenitors in the white matter and the subventricular zone are the major population of cycling cells in the postnatal central nervous system, and thought to be candidates for glioma-initiating cells. However, less is known about the dividing cell populations in the brainstem than those in the cerebrum, leading to the lag of basic understanding of brainstem gliomas. We herein demonstrate much fewer cycling glial progenitors exist in the brainstem than in the cerebrum. We also show that infecting brainstem glial progenitors with PDGFB-green fluorescent protein (GFP)-expressing retrovirus induced tumors that closely resembled human malignant gliomas. Of note, brainstem tumors grew more slowly than cerebral tumors induced by the same retrovirus, and >80% tumor cells in the brainstem consisted of GFP-positive, infected progenitors while GFP-positive cells in the cerebral tumors were <20%. These indicate that cerebral tumors progressed rapidly by recruiting resident progenitors via paracrine mechanism whereas brainstem tumors grew more slowly by clonal expansion of the infected population. The cerebral and brainstem glial progenitors similarly showed reversible dedifferentiation upon PDGF stimulation in vitro and did not show the intrinsic difference in terms of the responsiveness to PDGF. We therefore suggest that slower, monoclonal progression pattern of the brainstem tumors is at least partly due to the environmental factors including the cell density of the glial progenitors. Together, these findings are the first implications regarding the cell-of-origin and the gliomagenesis in the brainstem.