Pleiotrophin Induces Transdifferentiation of Monocytes Into Functional Endothelial Cells

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Abstract
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 bloo... 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.

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