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(American Journal of Pathology. 2006;168:1710-1721.)
© 2006 American Society for Investigative Pathology

The Origin and in Vivo Significance of Murine and Human Culture-Expanded Endothelial Progenitor Cells

Emerson E. Sharpe, III^*, Amylynn A. Teleron^*, Bin Li^*, James Price^*, Mark S. Sands, Kathy Alford^* and Pampee P. Young^*

From the Departments of Pathology^* and Internal Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; the Veterans Medical Center, Nashville, Tennessee; and the Department of Internal Medicine, Washington University Medical School, St. Louis, Missouri

In adults highly purified populations of early hematopoietic progenitors or cells derived from ex vivo expanded unmobilized human peripheral blood mononuclear cells contribute to new blood vessel formation. However, the source of these culture-expanded endothelial progenitor cells (CE-EPCs) remains controversial. We demonstrate that ex vivo expansion of unmobilized human peripheral blood generated CE-EPCs with similar numbers, kinetics, and antigen expression profile as compared to plating unfractionated CD34⁺/lin^–-enriched bone marrow mononuclear cells. Both CE-EPC populations uniformly co-expressed myeloid and endothelial markers, suggesting that peripheral blood progenitor enumeration does not correlate with the numbers of early outgrowth CE-EPCs. Using purified myeloid subpopulations obtained from mice harboring the lacZ transgene driven by an endothelial-specific promoter, we showed that the immature myeloid lineage marker CD31⁺ cells generated CE-EPCs with fourfold greater frequency than mature myeloid populations. Biphenotypic cells co-expressing myeloid/endothelial antigens were not detected in circulating human or murine peripheral blood or bone marrow but were associated with murine tumors. Unlike CE-EPCs, CD14⁺ leukocytes admixed within tumors did not generate vWF-positive blood vessels during a similarly defined period of tumor growth, but some leukocytes up-regulated the endothelial marker VE-cadherin. Taken together, the data suggest that the local neovascular microenvironment may facilitate vasculogenesis by promoting endothelial differentiation and that CE-EPCs may accelerate such vasculo-genesis.

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