Abstract
BackgroundAcquisition of a blood supply is fundamental for extensive tumor growth. We recently described vascular heterogeneity in tumours derived from cell clones of a human mesenchymal stem cell (hMSC) strain (hMSC-TERT20) immortalized by retroviral vector mediated human telomerase (hTERT) gene expression. Histological analysis showed that cells of the most vascularized tumorigenic clone, -BD11 had a pericyte-like alpha smooth muscle actin (ASMA+) and CD146+ positive phenotype. Upon serum withdrawal in culture, -BD11 cells formed cord-like structures mimicking capillary morphogenesis. In contrast, cells of the poorly tumorigenic clone, -BC8 did not stain for ASMA, tumours were less vascularized and serum withdrawal in culture led to cell death. By exploring the heterogeneity in hMSC-TERT20 clones we aimed to understand molecular mechanisms by which mesenchymal stem cells may promote neovascularization.Methodology/Principal FindingsQuantitative qRT-PCR analysis revealed similar mRNA levels for genes encoding the angiogenic cytokines VEGF and Angiopoietin-1 in both clones. However, clone-BD11 produced a denser extracellular matrix that supported stable ex vivo capillary morphogenesis of human endothelial cells and promoted in vivo neovascularization. Proteomic characterization of the -BD11 decellularized matrix identified 50 extracellular angiogenic proteins, including galectin-1. siRNA knock down of galectin-1 expression abrogated the ex vivo interaction between decellularized -BD11 matrix and endothelial cells. More stable shRNA knock down of galectin-1 expression did not prevent -BD11 tumorigenesis, but greatly reduced endothelial migration into -BD11 cell xenografts.ConclusionsDecellularized hMSC matrix had significant angiogenic potential with at least 50 angiogenic cell surface and extracellular proteins, implicated in attracting endothelial cells, their adhesion and activation to form tubular structures. hMSC -BD11 surface galectin-1 expression was required to bring about matrix-endothelial interactions and for xenografted hMSC -BD11 cells to optimally recruit host vasculature.
Highlights
Bone marrow derived human mesenchymal stem cell (hMSC) may have a supportive role in tumorigenesis [1], even possibly an ontogenic role in Ewing’s sarcomas [2] where angiogenesis and vasculogenesis are prominent
Decellularized hMSC matrix had significant angiogenic potential with at least 50 angiogenic cell surface and extracellular proteins, implicated in attracting endothelial cells, their adhesion and activation to form tubular structures. hMSC -BD11 surface galectin-1 expression was required to bring about matrix-endothelial interactions and for xenografted hMSC -BD11 cells to optimally recruit host vasculature
Cell signalling is mediated via adhesion receptors such as integrins, sequestered growth factors [6] and mechanical characteristics of the matrix, which combine to influence endothelial cell differentiation, PLoS ONE | www.plosone.org hMSC Extracellular Matrix Proteins and Vasculature survival, polarity and migration [7]
Summary
Bone marrow derived hMSC may have a supportive role in tumorigenesis [1], even possibly an ontogenic role in Ewing’s sarcomas [2] where angiogenesis and vasculogenesis are prominent. Since tumorigenic cells can acquire a blood supply via distinct processes, detailed understanding of the specific molecular mechanisms involved is required for appropriate therapeutic strategies. Angiogenesis (new blood vessels from pre-existing vessels), or tumour vasculogenesis (recruitment of bone marrow endothelial progenitor cells to form de novo vessels) are influenced by vascular endothelial growth factor (VEGF) [4]. Cell signalling is mediated via adhesion receptors such as integrins, sequestered growth factors [6] and mechanical characteristics of the matrix, which combine to influence endothelial cell differentiation, PLoS ONE | www.plosone.org hMSC Extracellular Matrix Proteins and Vasculature survival, polarity and migration [7]. Cells of the poorly tumorigenic clone, -BC8 did not stain for ASMA, tumours were less vascularized and serum withdrawal in culture led to cell death. By exploring the heterogeneity in hMSC-TERT20 clones we aimed to understand molecular mechanisms by which mesenchymal stem cells may promote neovascularization
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