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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:1273.)
© 2006 American Heart Association, Inc.

Vascular Biology

Pleiotrophin Induces Transdifferentiation of Monocytes Into Functional Endothelial Cells

Behrooz G. Sharifi; Zhaohui Zeng; Lai Wang; Lei Song; Haiming Chen; Minghui Qin; M. Rocio Sierra-Honigmann; Sebastian Wachsmann-Hogiu; Prediman K. Shah

From the Atherosclerosis Research Center (B.G.S., Z.Z., L.W., L.S., H.C., M.Q., P.K.S.), Division of Cardiology, and Department of Surgery (M.R.S.-H., S.W.-H.), Burns and Allen Research Institute, Cedars-Sinai Medical Center, Los Angeles, Calif.

Correspondence to Behrooz G. Sharifi, PhD, Cedars-Sinai Medical Center, Davis Building 1016, 8700 Beverly Blvd, Los Angeles, CA 90048. E-mail Sharifi{at}cshs.org

Objective— Pleiotrophin (PTN) is a cytokine that is expressed by monocytes/macrophages in ischemic tissues and that promotes neovascularization, presumably by stimulating proliferation of local endothelial cells. However, the effect of PTN on monocytes/macrophages remains unknown. We investigated the role of PTN in regulating the phenotype of monocytes/macrophages.

Methods and Results— RT-PCR, real-time PCR, and fluorescence-activated cell sorter analysis revealed that the expression of PTN by monocytic cells led to a downregulation of CD68, c-fms, and CD14 monocytic cell markers and an upregulation of FLK-1, Tie-2, vascular endothelial-cadherin, platelet endothelial cell adhesion molecule-1, endothelial NO synthase, von Willebrand factor, CD34, GATA-2, and GATA-3 endothelial cell markers. Fibrin gel assays showed that the treatment of mouse and human monocytic cells with PTN led to the formation of tube-like structures. In vivo studies showed that PTN-expressing monocytic cells incorporated into the blood vessels of the quail chorioallantoic membrane. The intracardial injection of PTN-expressing monocytic cells into chicken embryos showed that cells integrated only into the developing vasculature. Finally, the injection of PTN-expressing monocytes into a murine ischemic hindlimb model significantly improved perfusion of the ischemic tissue.

Conclusions— PTN expression by monocytes/macrophages led to a downregulation of their monocytic cell markers and an upregulation of endothelial cell characteristics, thus inducing the transdifferentiation of monocytes into functional endothelial cells.

Pleiotrophin (PTN) is a cytokine that is expressed by monocytes/macrophages in the highly vascularized regions of ischemic tissues. We investigated whether exposure of monocytes/macrophages to PTN alter the phenotype of these cells. Using multiple of in vitro and in vivo approaches, we found that exposure of monocytes/macrophages led to downregulation of cell phenotype and upregulation of endothelial cell characteristics. These transdifferentiated cells incorporated into newly developed vasculature and increased blood flow into ischemic hindlimb.

Key Words: transdifferentiation • pleiotrophin • macrophage • endothelial cell

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