Prostaglandin E positively modulates endothelial progenitor cell homeostasis: an advanced treatment modality for autologous cell therapy.
OBJECTIVE
The mobilization of endothelial progenitor cells (EPC) and their functioning in postnatal neovascularization are tightly regulated. To identify new modulators of EPC homeostasis, we screened biologically active prostaglandin E compounds for their effects on EPC production, trafficking and function.


RESULTS
We found that EPC are a rich source for prostaglandin E(2) (PGE(2)), stimulating their number and function in an auto- and paracrine manner. In vivo blockade of PGE(2) production by selective cyclooxygenase-2 inhibition virtually abrogated ischemia-induced EPC mobilization demonstrating its crucial role in EPC homeostasis following tissue ischemia. Conversely, ex vivo treatment of isolated EPC with the clinically approved PGE(1) analogue alprostadil enhanced EPC number and function. These effects were mediated by increased expression of the chemokine receptor CXCR4 and were dependent on nitric oxide synthase activity. Most importantly, ex vivo PGE(1) pretreatment of isolated EPC significantly enhanced their neovascularization capacity in a murine model of hind limb ischemia as assessed by laser Doppler analysis, exercise stress test and immunohistochemistry.


CONCLUSIONS
The conserved role for PGE in the regulation of EPC homeostasis suggests that ex vivo modulation of the prostaglandin pathway in isolated progenitor cells may represent a novel and safe strategy to facilitate cell-based therapies.
Herrler
Tanja
T
Department of Surgery, Experimental Medicine, Ludwig Maximilian University, Munich, Germany.
Leicht
Simon F
SF
Huber
Stephan
S
Hermann
Patrick C
PC
Schwarz
Theresa M
TM
Kopp
Reinhard
R
Heeschen
Christopher
C
D000328:Adult; D000368:Aged; D000527:Alprostadil / Q000494:pharmacology; D000818:Animals; D016022:Case-Control Studies; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D003327:Coronary Disease / Q000378:metabolism / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D003920:Diabetes Mellitus / Q000378:metabolism / Q000473:pathology; D015232:Dinoprostone / Q000378:metabolism*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006614:Hindlimb; D006706:Homeostasis; D006801:Humans; D007511:Ischemia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000098:blood supply; D018919:Neovascularization, Physiologic; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D033581:Stem Cell Transplantation / Q000379:methods*; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D014182:Transplantation, Autologous; D055815:Young Adult
C527276:CXCR4 protein, human; D052246:Cyclooxygenase 2 Inhibitors; D019718:Receptors, CXCR4; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D000527:Alprostadil; D015232:Dinoprostone