Glioblastoma Stem Cells Generate Vascular Pericytes to Support Vessel Function and Tumor Growth.pdf

Glioblastoma Stem Cells Generate Vascular Pericytes to Support Vessel Function and Tumor Growth Lin Cheng,1,7 Zhi Huang,1,7 Wenchao Zhou,1 Qiulian Wu,1 Shannon Donnola,1 James K. Liu,2 Xiaoguang Fang,1 Andrew E. Sloan,3 Yubin Mao,4 Justin D. Lathia,1 Wang Min,5 Roger E. McLendon,6 Jeremy N. Rich,1 and Shideng Bao1,* 1Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute 2Department of Neurosurgery Cleveland Clinic, Cleveland, OH 44195, USA 3Brain Tumor and Neuro-Oncology Center, University Hospitals, Case Western Reserve University, Cleveland, OH 44106, USA 4Department of Pathology, Medical College of Xiamen University, Xiamen, Fujian 361005, China 5Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA 6Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA 7These authors contributed equally to this work *Correspondence: baos@ /10.1016/j.cell.2013.02.021SUMMARY Glioblastomas (GBMs) are highly vascular and lethal brain tumors that display cellular hierarchies contain- ing self-renewing tumorigenic glioma stem cells (GSCs). Because GSCs often reside in perivascular niches and may undergo mesenchymal differentia- tion, we interrogated GSC potential to generate vascular pericytes. Here, we show that GSCs give rise to pericytes to support vessel function and tumor growth. In vivo cell lineage tracing with constitutive and lineage-specific fluorescent reporters demon- strated that GSCs generate the majority of vascular pericytes. Selective elimination of GSC-derived peri- cytes disrupts the neovasculature and potently inhibits tumor growth. Analysis of human GBM spec- imens showed that most pericytes are derived from neoplastic cells. GSCs are recruited toward endothe- lial cells via the SDF-1/CXCR4 axis and are induced to become pericytes predominantly by transforming growth factor b. Thus, GSCs contribute to vascular pericytes that may actively remodel perivascular niches. Therapeutic