Endothelial Differentiation Potential of Human Monocyte-derived Multipotential Cells

¹ Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan; Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan
² Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
³ Division of Cardiology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
⁴ Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan
⁵ Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan

^* To whom correspondence should be addressed. E-mail: kuwanam{at}sc.itc.keio.ac.jp.

	Abstract

We previously reported a unique CD14⁺CD45⁺CD34⁺type I collagen⁺ cell fraction derived from human circulating CD14⁺ monocytes, named monocyte-derived multipotential cells (MOMCs). This primitive cell population contains progenitors capable of differentiating along the mesenchymal and neuronal lineages. Here, we investigated whether MOMCs can also differentiate along the endothelial lineage. MOMCs treated with angiogenic growth factors for 7 days changed morphologically and adopted a caudate appearance with rod-shaped microtubulated structures resembling Weibel-Palade bodies. Almost every cell expressed CD31, CD144, vascular endothelial growth factor (VEGF) type 1 and 2 receptors, Tie-2, von Willebrand factor (vWF), endothelial nitric oxide synthase, and CD146, but CD14/CD45 expression was markedly down-regulated. Under these culture conditions, the MOMCs continued to proliferate for up to 7 days. Functional characteristics, including vWF release upon histamine stimulation and up-regulated expression of VEGF and VEGF type 1 receptor in response to hypoxia, were indistinguishable between the MOMC-derived endothelial-like cells and cultured mature endothelial cells. The MOMCs responded to angiogenic stimuli and promoted the formation of mature endothelial cell tubules in Matrigel® cultures. Finally, in xenogenic transplantation studies using a SCID mouse model, syngeneic colon carcinoma cells were injected subcutaneously with or without human MOMCs. Co-transplantation of the MOMCs promoted the formation of blood vessels, and more than 40% of the tumor vessel sections incorporated human endothelial cells derived from MOMCs. These findings indicate that human MOMCs can proliferate and differentiate along the endothelial lineage in a specific permissive environment, and thus represent an autologous transplantable cell source for therapeutic neovasculogenesis.

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