Immunoregulatory Roles of Tumor-Originated Pericytes Identified by Single-Cell Analysis in Glioblastoma

Pericytes as critical vascular support cells not only keep the integrity of blood-brain barrier but also play profound roles in brain tumors. Yet the origin and functional heterogeneity of pericytes in the most common malignant brain tumor glioblastoma (GBM) remain unclear. Here, single-cell RNA-sequencing (scRNA-seq) is performed on CD146⁺ pericytes from human primary GBMs. Tumor- and normal-originated pericytes (T-PCs and N-PCs) that have distinctive cell-intrinsic features and intercellular communications with endothelial and immune cells are identified. Bioinformatic analyses on integrated in-house and public scRNA-seq data have found a T-PC metacluster marked by CD44 closely associated with tumor-associated macrophages (TAMs). The CD44^High pericytes are detected in human GBM samples and glioma-stem-cell (GSC)-derived pericytes. Coimplantation of GSC-derived CD44^High pericytes promotes M2 polarization of TAMs and growth of orthotopic GBMs. In summary, this study unravels the existence of T-PCs and N-PCs in GBMs, analyzes their functional heterogeneity, and unravels the immunoregulatory roles of CD44^High pericytes. These discoveries help to gain insights into brain tumor vasculature and inspire therapeutic strategies targeting vessels and TAMs for GBM treatment.