Abstract
Vasculogenesis is a physiologic process typical of fetal development in which new blood vessels develop from undifferentiated precursors (or angioblasts). In tumors, near angiogenesis, vasculogenesis contributes to the formation of the microvascular plexus that is important for diffusion. Here, we show that hematopoietic stem and progenitor cells (HSPC) of multiple myeloma (MM) patients are able to differentiate into cells with endothelial phenotype on exposure to angiogenic cytokines. Circulating HSPCs were purified with an anti-CD133 antibody from patients with newly diagnosed MM before autologous transplantation and exposed to vascular endothelial growth factor (VEGF), fibroblast growth factor-2 and insulin-like growth factor in a 3-week culture. HSPCs gradually lost CD133 expression and acquired VEGF receptor-2, factor VIII-related antigen, and vascular endothelial-cadherin expression. The expression pattern overlapped with paired MM endothelial cells (MMEC). During culture, cells adhered to fibronectin, spread, and acquired an endothelial cell shape. Differentiated HSPCs also became capillarogenic in the Matrigel assay with maximal activity at the third week of culture. Bone marrow biopsies revealed HSPCs inside the neovessel wall in patients with MM but not in those with monoclonal gammopathy of undetermined significance. In patients with MM, but not in those with monoclonal gammopathy of undetermined significance, HSPCs contribute to the neovessel wall building together with MMECs. Therefore, besides angiogenesis, HSPC-linked vasculogenesis contributes to neovascularization in MM patients. Tentatively, we hypothesize that in HSPC cultures a multipotent cell population expressing low VEGF receptor-2 levels corresponds to the endothelial progenitor cell precursor and seems to be the MMEC precursor.
Highlights
Vasculogenesis is a physiologic process typical of fetal development in which new blood vessels develop from undifferentiated precursors
Double staining revealed that 18.3 F 3.2% of CD133+ hematopoietic stem and progenitor cells (HSPC) expressed CD34 (Fig. 1B), 88.6 F 8.3% expressed Tie2/Tek (Fig. 1C), 7.6 F 1.6% expressed VEGFR-2 (Fig. 1D), and 1.2 F 0.8% expressed VEcadherin (Fig. 1E)
The marginal VEGFR-2 and VEcadherin expression indicated that CD133+ HSPCs were not orientated to endothelial cell differentiation
Summary
Vasculogenesis is a physiologic process typical of fetal development in which new blood vessels develop from undifferentiated precursors (or angioblasts). Extensive data support the existence of endothelial progenitor cells (EPC), their bone marrow origin, and contribution to the formation of new blood vessels in adult [3]. Their discovery led to the new concept that vasculogenesis and angiogenesis may occur simultaneously in the postnatal life because EPCs are able to differentiate through a mechanism recapitulating embryo vasculogenesis. In multiple myeloma (MM), bone marrow angiogenesis measured as microvascular density increases with progression from monoclonal gammopathy of undetermined significance (MGUS) to MM and is related with the plasma cell labeling index [6]. It has been suggested that the presence of EPCs in patients with MM correlates with clinical outcome [8]
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