Mesenchymal stem cells and fibroblasts contribute to microvascular proliferation in glioblastoma and are correlated with immunosuppression and poor outcome

Abstract Microvascular proliferation (MVP) is a disease-defining hallmark of glioblastoma (GBM) and other World Health Organization (WHO) grade 4 gliomas. MVP also serves as a poor prognostic marker in various solid tumors. Despite its clinical significance, the mechanisms and biological consequences of MVP are controversial and remain unclear. In this study, we performed single cell RNA-sequencing (scRNA-seq) on paired CD45-CD105+ vascular/perivascular stromal cells (PVSCs) and CD45+CD105± immune cells from 16 primary glioma patient samples, both with and without MVP. This analysis revealed the presence of developmentally-related mesenchymal stem cells (MSCs) alongside cancer-associated fibroblasts (CAFs), pericytes, fibromyocytes, and smooth muscle cells within the CD45-CD105+ compartment. RNA velocity analysis identified PDGFRB as a putative driver gene guiding MSCs toward more mature PVSCs in the context of MVP. Signaling network analysis and digital spatial profiling uncovered interactions between PDGFRB+ PVSCs and immunosuppressive myeloid cell subsets enriched in the perivascular niche, suggesting targetable receptor–ligand interactions. Additionally, a gene signature of MVP-associated PVSCs from gliomas predicted worse prognosis in multiple other solid tumors. This study provides a transcriptomic cell atlas of PVSCs and immune cells in glioma, helping to refine the biological model of MVP which has traditionally focused on endothelial cells.