Priming with angiopoietin-1 augments the vasculogenic potential of the peripheral blood stem cells mobilized with granulocyte colony-stimulating factor through a novel Tie2/Ets-1 pathway.
BACKGROUND
The low engraftment rate of stem/progenitor cells infused via the intracoronary route to the ischemic myocardium is one of the most important factors limiting the efficacy of cell therapy. We investigated the concept of priming peripheral blood stem cells enriched by granulocyte colony-stimulating factor mobilization and apheresis ((mob)PBSCs) with angiopoietin-1 (Ang1), to enhance the engraftment into the ischemic tissue and neovasculogenic potential.


RESULTS
The expression of Tie2, the Ang1 receptor, was significantly higher in (mob)PBSCs than naïve peripheral blood mononuclear cells (19.2+/-3.0% versus 1.2+/-0.8% versus 1.2+/-0.2%; P<0.001 for (mob)PBSCs from acute myocardial infarction (AMI) patients with granulocyte colony-stimulating factor treatment for 3 days versus peripheral blood mononuclear cells from AMI patients versus peripheral blood mononuclear cells from stable angina patients). After 4 hours of cartilage oligomeric matrix protein (COMP)-Ang1 stimulation, (mob)PBSCs committed to the endothelial lineage with the induction of CD31 and VE-cadherin expression, mediated by Tie2/Ets-1 pathway. Priming of (mob)PBSCs with COMP-Ang1 induced the expression of alpha4beta1 and alpha5beta1 integrins, which are also Ets-1 downstream molecules, leading to enhanced adhesion to endothelial cells or fibronectin. In a rabbit ear ischemia/reperfusion model, priming of (mob)PBSCs with COMP-Ang1 improved first-pass engraftment to the distal vascular bed after intraarterial delivery. In a murine ischemic hind-limb model, intravascular delivery of primed (mob)PBSCs enhanced both engraftment and neovascularization.


CONCLUSIONS
The short-term priming with COMP-Ang1 may be a feasible and promising option to activate (mob)PBSCs by enhancing differentiation and adhesiveness and to improve the efficacy of cell therapy for ischemic diseases.
Kim
Min-Seok
MS
National Research Laboratory for Cardiovascular Stem Cell, Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul 110-744, Korea.
Lee
Choon-Soo
CS
Hur
Jin
J
Cho
Hyun-Jai
HJ
Jun
Soo-In
SI
Kim
Tae-Youn
TY
Lee
Sae-Won
SW
Suh
Jung-Won
JW
Park
Kyung-Woo
KW
Lee
Hae-Young
HY
Kang
Hyun-Jae
HJ
Lee
Dong-Soo
DS
Koh
Gou-Young
GY
Nakagami
Hironori
H
Morishita
Ryuichi
R
Park
Young-Bae
YB
Kim
Hyo-Soo
HS
D042683:Angiopoietin-1 / Q000494:pharmacology*; D000818:Animals; D001781:Blood Component Removal; D019070:Cell Lineage / Q000187:drug effects / Q000502:physiology; D003094:Collagen; D004195:Disease Models, Animal; D004338:Drug Combinations; D004431:Ear, External / Q000098:blood supply; D042783:Endothelial Cells / Q000166:cytology; D005434:Flow Cytometry; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D019650:Hematopoietic Stem Cell Mobilization / Q000379:methods*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D006614:Hindlimb / Q000098:blood supply; D006801:Humans; D039041:Integrin alpha4beta1 / Q000378:metabolism; D039081:Integrin alpha5beta1 / Q000378:metabolism; D007797:Laminin; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology; D011509:Proteoglycans; D050784:Proto-Oncogene Protein c-ets-1 / Q000378:metabolism*; D011817:Rabbits; D042787:Receptor, TIE-2 / Q000378:metabolism*; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
C467630:ANGPT1 protein, human; D042683:Angiopoietin-1; D004338:Drug Combinations; C494041:ETS1 protein, human; D039041:Integrin alpha4beta1; D039081:Integrin alpha5beta1; D007797:Laminin; D011509:Proteoglycans; D050784:Proto-Oncogene Protein c-ets-1; C059485:matrigel; D016179:Granulocyte Colony-Stimulating Factor; D003094:Collagen; D042787:Receptor, TIE-2