A Comparative Immunofluorescence Study Demonstrating that Peri‐arteriolar Glioma Stem Cell Niches in Human Glioblastoma are a Mimic of Peri‐arteriolar Hematopoietic Stem Cell Niches in Human Bone Marrow

Abstract

Glioblastoma is the most aggressive type of brain tumor with poor patient survival. A fraction of glioblastoma cells within glioblastoma tumors consists of slowly dividing and therefore therapy‐resistant glioma stem cells (GSCs) residing in protective peri‐arteriolar niches and are held responsible for tumor recurrence. The hypothesis of this study is that GSC niches are a mimic of hematopoietic stem cell (HSC) niches in human bone marrow as in both types of niches, similar niche factors and molecular interactions are involved in retention and release of stem cells. Immunofluorescence was performed on paraffin sections of 10 glioblastoma patient samples and 2 human bone marrow samples to localize GSC niches and HSC niches and to determine whether the two types of niches are similar or not. Smooth muscle actin (SMA) was used to detect smooth muscle cells in the arteriolar wall. The markers CD133 and CD150 were used as HSC markers and CD244 as hematopoietic progenitor cell marker. CD133 and SOX2 were used as markers to detect GSCs and CD105 and CD73 were used as markers to detect mesenchymal stem cells (MSCs). In addition, expression of chemoattractants stromal‐derived factor‐1α (SDF‐1α) and osteopontin (OPN), and their receptors, C‐X‐C receptor type 4 (CXCR4) and CD44, respectively, was localized. Expression of hypoxia‐inducible factor(HIF)‐1α, HIF‐2α and vascular endothelial growth factor (VEGF) was localized to determine hypoxic conditions. We found CD133‐CD150‐CXCR4‐CD44‐positive HSCs localized adjacent to bone around SMA‐positive arterioles in SDF‐1α‐ and OPN‐rich niches. CD244‐positive hematopoietic progenitor cells were localized at a distance from bone near sinusoids. CD105‐ and CD73‐positive MSCs were localized in peri‐arteriolar niches as well. Expression of HIF‐1α, HIF‐2α and VEGF confirmed hypoxia. Similarly, we found CD133‐SOX2‐CXCR4‐CD44‐positive GSCs around SMA‐positive arterioles in SDF‐1α‐ and OPN‐rich niches. CD105‐positive MSCS were localized around the arterioles. Hypoxic conditions were confirmed by HIF‐1α, HIF‐2α and VEGF expression in GSC niches. In both niche types, SDF‐1α and OPN retain HSCs and GSCs in hypoxic peri‐arteriolar niches by interacting with their receptors CXCR4 and CD44 on the HSCs and GSCs, respectively. MSCs are major SDF‐1α producers, attracting and maintaining HSCs and GSCs in niches. We conclude that GSC niches in glioblastoma are a mimic of HSC niches in bone marrow. We aim to disrupt interactions between GSCs and their protective niches to induce GSC differentiation and proliferation to render GSCs more sensitive to anti‐glioblastoma therapies.Support or Funding InformationKWF; UVA 2014‐6839This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.