Pleiotrophin induces transdifferentiation of monocytes into functional endothelial cells.
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.


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.
Sharifi
Behrooz G
BG
Atherosclerosis Research Center, Burns and Allen Research Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA. Sharifi@cshs.org
Zeng
Zhaohui
Z
Wang
Lai
L
Song
Lei
L
Chen
Haiming
H
Qin
Minghui
M
Sierra-Honigmann
M Rocio
MR
Wachsmann-Hogiu
Sebastian
S
Shah
Prediman K
PK
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001808:Blood Vessels / Q000166:cytology; D002352:Carrier Proteins / Q000494:pharmacology / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D002642:Chick Embryo / Q000098:blood supply; D049033:Chorioallantoic Membrane / Q000098:blood supply; D003370:Coturnix; D016207:Cytokines / Q000494:pharmacology / Q000502:physiology*; D015536:Down-Regulation; D042783:Endothelial Cells / Q000166:cytology* / Q000502:physiology*; D018014:Gene Transfer Techniques; D006614:Hindlimb / Q000098:blood supply; D006801:Humans; D007511:Ischemia / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D010641:Phenotype; D046509:Tissue Culture Techniques; D014158:Transcription, Genetic / Q000502:physiology; D015854:Up-Regulation
D015415:Biomarkers; D002352:Carrier Proteins; D016207:Cytokines; C066845:pleiotrophin