DOI: 10.1002/ame2.70073
Insight into pericytes in glioblastoma angiogenesis:In vivo tracking by two-photon microscopy and proteomic profiling
Qinghong Wang
Chengyan Ma
Xinpei Wang
Mengyuan Li
Xingjiu Yang
Ran Gao
Institute of Laboratory Animal Science,CAMS&PUMC,National Human Diseases Animal Model Resource Center,National Center of Technology Innovation for Animal Model,Beijing,China;State Key Laboratory of Respiratory Health and Multimorbidity,CAMS&PUMC,Beijing,China;NHC Key Laboratory of Comparative Medicine,CAMS&PUMC,Beijing,China
摘要：Background:Glioblastoma(GBM)is a highly aggressive brain tumor characterized by aberrant angiogenesis and an immunosuppressive microenvironment.Pericytes are aberrantly recruited but their spatiotemporal roles and molecular changes remain un-clear.This study investigated platelet-derived growth factor receptor beta-positive(Pdgfrb+)pericyte dynamics and reprogramming in GBM vasculature.
Methods:We generated GL261-Luc and GL261-CFP glioblastoma cells via lentivi-ral transduction and established two transgenic models.(1)For pericyte labeling,Ai14 reporter mice was crossed with PDGFRβ-P2A-CreER T2 mice for tdTomato-specific lineage tracing(PT mice).(2)For conditional ablation,we generated inducible Pdgfrb-expressing cell ablation models(PT mice was crossed with ROSA-DTA mice).An intravital imaging platform(FITC-dextran/CFP/tdTomato+two-photon microscopy)tracked pericytes,vessels,and tumor cells,while FACS-sorted Pdgfrb+cells from GBM and normal brain were analyzed by LC-MS/MS proteomics.
Results:Cre-mediated ablation of Pdgfrb-expressing cells revealed stage-dependent effects on GBM growth:early ablation inhibited progression while late ablation pro-moted it.Pericytes undergo dual spatial reorganization in GBM:regional enrichment with pre-sprouting accumulation at the tumor-brain interface,and focal positioning with preferential localization at vascular branch points.Concurrently,GBM vascula-ture displayed simplified branching,dilation,and pericyte remodeling(shorter pro-cesses,higher density).Proteomics revealed 1426 altered proteins,with upregulated proliferation pathways(e.g.,matrix metallopeptidase 14[Mmp14],lysyl oxidase like 2[Loxl2])and downregulated homeostasis functions(e.g.,transforming growth factor beta 1[Tgfb1]),validated by scRNA-seq in human GBM.
Conclusions:This study demonstrates that during early GBM progression,peri-cytes actively drive tumor angiogenesis through molecular reprogramming toward proliferative and pro-angiogenic phenotypes,with the integrated imaging-proteomics framework revealing potential therapeutic targets for disrupting pericyte-mediated vascular remodeling.
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论文发表日期：2025-09-30
在线出版日期：2025-10-28（本平台首次上网日期，不代表文献的发表时间）
页数：12( 1688-1699 )
英文信息