Increased expression of CXCR4 and integrin alphaM in hypoxia-preconditioned cells contributes to improved cell retention and angiogenic potency.
Cell-based angiogenesis is a promising method for the treatment of ischemic diseases, but the poor retention of implanted cells in targeted tissues is a major drawback. We tested whether hypoxic preconditioning increased retention and angiogenic potency of implanted cells in ischemic tissue. Hypoxic preconditioning of mouse peripheral blood mononuclear cells (PBMNCs) was done with 24 h of culture under 2% O(2). Normoxia-cultured PBMNCs were used as a control. Hypoxic preconditioning increased the adhesion capacity of the PBMNCs. Moreover, the expression of integrin alphaM and CXCR4 was significantly higher in the hypoxia-preconditioned PBMNCs than in the normoxia-cultured PBMNCs. Interestingly, the expression of intercellular adhesion molecule-1 (ICAM-1), a ligand of integrin alphaM, and stromal cell-derived factor-1 (SDF-1), a chemokine for CXCR4, were remarkably increased in the ischemic hindlimbs. The retention of the hypoxia-preconditioned PBMNCs was significantly higher than that of the normoxia-cultured PBMNCs, 3 days after their intramuscular implantation into ischemic hindlimbs. We also noted better blood flow in the ischemic hindlimbs implanted with the hypoxia-preconditioned PBMNCs than in those implanted with the normoxia-cultured PBMNCs, 14 days after treatment. Furthermore, antibody neutralization of integrin alphaM and CXCR4 abolished completely the increased cell retention and angiogenic potency of the hypoxia-preconditioned PBMNCs after implantation into the ischemic hindlimbs. These results indicate that hypoxic preconditioning of implanted cells is a feasible method of enhancing therapeutic angiogenesis by increasing their retention.
Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan.
Masayuki
M
Kubo
Tao-Sheng
TS
Li
Takahiro
T
Kamota
Mako
M
Ohshima
Shu-Lan
SL
Qin
Kimikazu
K
Hamano
D000818:Animals; D039481:CD11b Antigen / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia; D017690:Cell Transplantation; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism; D002633:Chemotaxis / Q000502:physiology; D006614:Hindlimb / Q000098:blood supply; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D019194:Ischemic Preconditioning; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D046228:Microarray Analysis; D018919:Neovascularization, Physiologic; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D012039:Regional Blood Flow
D039481:CD11b Antigen; C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; D018799:Intercellular Adhesion Molecule-1