title: Injectable cell scaffold restores impaired cell-based therapeutic angiogenesis in diabetic mice with hindlimb ischemia.
abstract: The clinical success of cell-based therapeutic angiogenesis has been limited in diabetic patients with critical limb ischemia. We previously reported that an injectable cell scaffold (ICS), which is a nano-scaled hydroxyapatite (HAp)-coated polymer microsphere, enhances therapeutic angiogenesis. Subsequently, we developed a modified ICS for clinical use, measuring 50 μm in diameter using poly(l-lactide-co-ε-caprolactone) as a biodegradable polymer, which achieved appropriately accelerated absorption in vivo. The aim of the present study was to evaluate the effectiveness of this practical ICS in diabetic hindlimb ischemia. Bone-marrow mononuclear cells (BMNCs) were intramuscularly injected, without or with a practical ICS, into the ischemic hindlimbs of mice (BMNCs or ICS+BMNCs group, respectively). Kaplan-Meier analysis demonstrated that the beneficial effects of BMNC transplantation for limb salvage after ischemic surgery were almost entirely abrogated in streptozotocin-induced diabetic mice. In contrast, injection of ICS+BMNCs revealed significant limb salvage in diabetic mice to a similar extent as in non-diabetic mice. The number of apoptotic transplanted BMNCs was 1.8-fold higher in diabetic mice 10 days after transplantation compared to non-diabetic mice, while that in the ICS+BMNCs group was markedly lower (8.3% of that in the BMNCs group) even in diabetic mice. The proangiogenic factors VEGF and FGF2, also known as antiapoptotic factors, mostly co-localized with transplanted GFP-positive BMNCs that were closely aggregated around the ICS in ischemic tissue. In conclusion, the practical ICS significantly augmented cell-based therapeutic angiogenesis even in diabetic animals, through local accumulation of proangiogenic factors and antiapoptotic effects in transplanted cells.
authors.affiliation: Department of Metabolism, Endocrinology, and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Takeda
authors.affiliation: Department of Premier Preventive Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan. Electronic address: sfukumoto@med.osaka-cu.ac.jp.
authors.forename: Shinya
authors.initials: S
authors.lastname: Fukumoto
authors.affiliation: Department of Metabolism, Endocrinology, and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Koka
authors.initials: K
authors.lastname: Motoyama
authors.affiliation: Department of Metabolism, Endocrinology, and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Morioka
authors.affiliation: Department of Metabolism, Endocrinology, and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Katsuhito
authors.initials: K
authors.lastname: Mori
authors.affiliation: Department of Radiology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Kageyama
authors.affiliation: Department of Radiology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Yukimasa
authors.initials: Y
authors.lastname: Sakai
authors.affiliation: Gunze limited, Osaka, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Sato
authors.affiliation: Gunze limited, Osaka, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Department of Internal Medicine, Division of Diabetes, Endocrinology and Metabolism, Hyogo College of Medicine, Hyogo, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Koyama
authors.affiliation: Department of Geriatrics and Vascular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Shoji
authors.affiliation: Department of Nephrology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Ishimura
authors.affiliation: Department of Metabolism, Endocrinology, and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Emoto
authors.affiliation: Department of Biomedical Engineering, School of Biology-Oriented Science and Technology, Kinki University, Wakayama, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Furuzono
authors.affiliation: Department of Immunology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Nakajima
authors.affiliation: Department of Metabolism, Endocrinology, and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Inaba
mesh_terms: D015901:Angiography, Digital Subtraction; D000818:Animals; D017209:Apoptosis; D016026:Bone Marrow Transplantation / Q000379:methods; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000628:therapy*; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D006614:Hindlimb / Q000098:blood supply; D007273:Injections, Intramuscular; D007511:Ischemia / Q000000981:diagnostic imaging / Q000209:etiology* / Q000628:therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D055806:Microvessels / Q000000981:diagnostic imaging / Q000254:growth & development / Q000378:metabolism; D018919:Neovascularization, Physiologic; D011817:Rabbits; D054457:Tissue Scaffolds; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D016222:Fibroblast Growth Factor 2
keywords: Cell transplantation; Diabetes; Limb ischemia; Nanotechnology; Scaffold; Therapeutic angiogenesis