Hypoxic preconditioning reinforces cellular functions of autologous peripheral blood-derived cells in rabbit hindlimb ischemia model.
Peripheral blood mononuclear cell (PBMNC) is one of powerful tools for therapeutic angiogenesis in hindlimb ischemia. However, traditional approaches with transplanted PBMNCs show poor therapeutic effects in severe ischemia patients. In this study, we used autograft models to determine whether hypoxic pretreatment effectively enhances the cellular functions of PBMNCs and improves hindlimb ischemia. Rabbit PBMNCs were cultured in the hypoxic condition. After pretreatment, cell adhesion, stress resistance, and expression of angiogenic factor were evaluated in vitro. To examine in vivo effects, we autografted preconditioned PBMNCs into a rabbit hindlimb ischemia model on postoperative day (POD) 7. Preconditioned PBMNCs displayed significantly enhanced functional capacities in resistance to oxidative stress, cell viability, and production of vascular endothelial growth factor. In addition, autologous transplantation of preconditioned PBMNCs significantly induced new vessels and improved limb blood flow. Importantly, preconditioned PBMNCs can accelerate vessel formation despite transplantation on POD 7, whereas untreated PBMNCs showed poor vascularization. Our study demonstrated that hypoxic preconditioning of PBMNCs is a feasible approach for increasing the retention of transplanted cells and enhancing therapeutic angiogenesis in ischemic tissue.
Department of Surgery and Clinical Science, Division of Cardiac Surgery, Yamaguchi University Graduate School of Medicine, Ube, Japan.
Tomoaki
T
Kudo
Department of Surgery and Clinical Science, Division of Cardiac Surgery, Yamaguchi University Graduate School of Medicine, Ube, Japan. Electronic address: toruhoso@yamaguchi-u.ac.jp.
Tohru
T
Hosoyama
Department of Surgery and Clinical Science, Division of Cardiac Surgery, Yamaguchi University Graduate School of Medicine, Ube, Japan.
Makoto
M
Samura
Department of Surgery and Clinical Science, Division of Cardiac Surgery, Yamaguchi University Graduate School of Medicine, Ube, Japan.
Shunsaku
S
Katsura
Department of Surgery and Clinical Science, Division of Cardiac Surgery, Yamaguchi University Graduate School of Medicine, Ube, Japan.
Arata
A
Nishimoto
Department of Surgery and Clinical Science, Division of Cardiac Surgery, Yamaguchi University Graduate School of Medicine, Ube, Japan.
Naruji
N
Kugimiya
Department of Blood Transfusion Regeneration and Cell Therapy Center, Yamaguchi University Graduate School of Medicine, Ube, Japan.
Yasuhiko
Y
Fujii
Department of Stem Cell Biology, Nagasaki University Graduate School of Biomedical Science, Nagasaki, Japan.
Tao-Sheng
TS
Li
Department of Surgery and Clinical Science, Division of Cardiac Surgery, Yamaguchi University Graduate School of Medicine, Ube, Japan.
Kimikazu
K
Hamano
D000818:Animals; D004195:Disease Models, Animal; D006614:Hindlimb / Q000098:blood supply*; D000860:Hypoxia / Q000503:physiopathology*; D007511:Ischemia / Q000097:blood*; D008297:Male; D011817:Rabbits
Cell-based therapy; Hypoxic preconditioning; Peripheral blood-derived mononuclear cells; Pre-clinical testing; Therapeutic angiogenesis