BACKGROUND: Glioblastoma (GBM) is the most lethal type of primary brain tumor with florid angiogenesis. GBMs display striking cellular hierarchies containing self-renewing glioma stem cells (GSCs) that are highly tumorigenic. GSCs not only produce elevated levels of VEGF to promote tumor angiogenesis but also contribute to cellular compartments of tumor vessels. METHODS: 1. In vivo cell lineage tracing with constitutive and Desmin promoter-driven GFP or RFP fluorescent reporters. 2. Selective elimination of GSC-derived pericytes with Desmin promoter-driven HsvTK. 3. GSC-derived GBM xenograft models. RESULTS: Cell lineage tracing with constitutive and lineage specific fluorescent reporters demonstrated that GSCs generate the majority of vascular pericytes in vivo. Selective elimination of GSC-derived pericytes disrupted tumor vessels and potently suppressed GSC tumor growth. Thus, GSCs can function as pericyte progenitors and contribute to vasculature formation and maintenance in GBMs. CONCLUSIONS: The ability of GSCs to generate the majority of pericytes allows active tumor angiogenesis to promote rapid tumor growth in GBMs. GSC-derived pericytes also play a critical role in the resistance to the anti-angiogenic therapy targeting endothelial cells only, suggesting that selective targeting of GSC-derived pericytes may significantly improve the efficacy and specificity of the anti-angiogenic treatment. SECONDARY CATEGORY: n/a.