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Endothelial Differentiation of Hematopoietic Stem and Progenitor Cells from Patients with Multiple Myeloma

Authors' Affiliations: Departments of ¹ Internal Medicine and Clinical Oncology and ² Human Anatomy and Histology, University of Bari Medical School; ³ Hematology Unit, Institute of Oncology "Giovanni Paolo II," Bari, Italy; ⁴ Department of Biochemistry, University of Foggia Medical School, Foggia, Italy; ⁵ Department of Hematology and Clinical Immunology, University of Perugia Medical School, Perugia, Italy; ⁶ Department of Human Anatomy and Physiology, University of Padova Medical School, Padova, Italy; ⁷ Department of Internal Medicine and Public Health, University of L'Aquila Medical School, L'Aquila, Italy; and ⁸ Unit of Hematology, Hospital "Vito Fazzi," Lecce, Italy

Requests for reprints: Angelo Vacca, Department of Internal Medicine and Clinical Oncology, University of Bari Medical School, Policlinico, Piazza Giulio Cesare, 11, I-70124 Bari, Italy. Phone: 39-080-559-34-44; Fax: 39-080-559-21-89; E-mail: a.vacca{at}dimo.uniba.it.

Purpose: 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.

Experimental Design: 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.

Results: 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.

Conclusions: 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.

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