Hematopoietic Stem Cell–Derived Pericytic Cells in Brain Tumor Angio-Architecture

Abstract

Bone marrow-derived cells are recruited into tumor vasculature in response to angiogenic signals, and some of the cells within the newly forming tumor vessels are hematopoietic stem cells (HSCs) in origin. Previous studies suggest that bone marrow-derived pericytes are associated with newly formed vessels in tumors. In this study, we used an orthotopic rat glioma model (RT-2/RAG) to examine the contribution of long-term hematopoietic stem cell (LT-HSC)-derived pericytic cells to brain tumor angiogenesis. Mice (RAG-2/KO5.2) were lethally irradiated, and their hematopoietic cells were repopulated by transplantation of double fluorescence-activated cell-sorted LT-HSCs that express green fluorescent protein (GFP+). RT-2/RAG cells were then injected into the striatum of the chimeric mice 6 weeks post-transplantation. The animals were sacrificed 9 days after tumor implantation, and the incorporation and lineage-specific marker expression profile of the GFP+ cells within the growing tumor and tumor periphery were analyzed. LT-HSC-derived GFP+ cells were noted to incorporate onto the surface of tumor vessels within the perivascular space. LT-HSC-derived GFP+ cells express the pericyte progenitor marker, platelet-derived growth factor receptor-beta (PDGFR beta), as well as mature perictyte markers such as nerve/glial antigen 2 proteoglycan (NG2), alpha-smooth muscle actin (alpha SMA), and desmin. These LT-HSC-derived cells may represent a population of progenitor or committed pericytes within the neovascular tree and may play a role in shaping the angio-architecture in the vascular niche of brain tumors.