title: Hypoxically preconditioned human peripheral blood mononuclear cells improve blood flow in hindlimb ischemia xenograft model.
abstract: Transplantation of peripheral blood mononuclear cells (PBMNCs) is a promising therapeutic approach for the treatment of hindlimb ischemia. However, insufficient angiogenesis in ischemic hindlimb after cell transplantation reduces the importance and practicality of this approach. Previously, we demonstrated using mouse models that hypoxic preconditioning augmented the cellular functions of rodent PBMNCs, such as increased cell adhesion capacity and accelerated neovascularization in ischemic hindlimb. To test the clinical application of this therapeutic strategy in this study, we investigated whether the protocol of hypoxic preconditioning, which was established in a condition of 2% O2 for 24 h, can be made available for human PBMNCs (hPBMNCs). In addition, we grafted preconditioned hPBMNCs in a hindlimb ischemia mouse model. Hypoxic preconditioning enhanced cell adhesion capacity and oxidative stress resistance in hPBMNCs. We also observed an up-regulation of platelet endothelial cell adhesion molecule-1 (PECAM-1) in hPBMNCs by hypoxic preconditioning. Furthermore, preconditioned hPBMNCs significantly recovered limb blood flow in ischemic mice after transplantation. These results indicate that our established preconditioning protocol is available for hPBMNCs to effectively reinforce multiple cellular functions. Taken together with our series of study, we believe that this simple but powerful therapeutic strategy will be helpful in curing patients with severe hindlimb ischemia.
authors.affiliation: Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Kudo
authors.affiliation: Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine Japan ; Department of Public Health, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kubo
authors.affiliation: Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine Japan.
authors.forename: Shunsaku
authors.initials: S
authors.lastname: Katsura
authors.affiliation: Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine Japan.
authors.forename: Arata
authors.initials: A
authors.lastname: Nishimoto
authors.affiliation: Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Ueno
authors.affiliation: Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Samura
authors.affiliation: Department of Blood Transfusion Regeneration and Cell Therapy Center, Yamaguchi University Graduate School of Medicine Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Fujii
authors.affiliation: Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Hosoyama
authors.affiliation: Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine Japan.
authors.forename: Kimikazu
authors.initials: K
authors.lastname: Hamano
keywords: Hindlimb ischemia; cell-based therapy; human peripheral blood mononuclear cells; hypoxic preconditioning; therapeutic angiogenesis