title: Ex vivo expansion of circulating CD34(+) cells enhances the regenerative effect on rat liver cirrhosis.
abstract: Ex vivo expansion of autologous cells is indispensable for cell transplantation therapy of patients with liver cirrhosis. The aim of this study was to investigate the efficacy of human ex vivo-expanded CD34(+) cells for treatment of cirrhotic rat liver. Recipient rats were intraperitoneally injected with CCl4 twice weekly for 3 weeks before administration of CD34(+) cells. CCl4 was then re-administered twice weekly for 3 more weeks, and the rats were sacrificed. Saline, nonexpanded or expanded CD34(+) cells were injected via the spleen. After 7 days, CD34(+) cells were effectively expanded in a serum-free culture medium. Expanded CD34(+) cells were also increasingly positive for cell surface markers of VE-cadherin, VEGF receptor-2, and Tie-2. The expression of proangiogenic growth factors and adhesion molecules in expanded CD34(+) cells increased compared with nonexpanded CD34(+) cells. Expanded CD34(+) cell transplantation reduced liver fibrosis, with a decrease of αSMA(+) cells. Assessments of hepatocyte and sinusoidal endothelial cell proliferative activity indicated the superior potency of expanded CD34(+) cells over non-expanded CD34(+) cells. The inhibition of integrin αvβ3 and αvβ5 disturbed the engraftment of transplanted CD34(+) cells and aggravated liver fibrosis. These findings suggest that expanded CD34(+) cells enhanced the preventive efficacy of cell transplantation in a cirrhotic model.
authors.affiliation: Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan; Liver Cancer Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan; Liver Cancer Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Koga
authors.affiliation: Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan; Liver Cancer Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Iwamoto
authors.affiliation: Department of Infectomics and Molecular Pathogenesis, Center for Research and Advanced Studies , Mexico City, Mexico.
authors.forename: Victor
authors.initials: V
authors.lastname: Tsutsumi
authors.affiliation: Liver Cancer Division, Research Center for Innovative Cancer Therapy, Kurume University , Kurume, Japan.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Imamura
authors.affiliation: Liver Cancer Division, Research Center for Innovative Cancer Therapy, Kurume University , Kurume, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Naitou
authors.affiliation: Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan; Liver Cancer Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Japan.
authors.forename: Atsutaka
authors.initials: A
authors.lastname: Masuda
authors.affiliation: Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan; Liver Cancer Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Ikezono
authors.affiliation: Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan; Liver Cancer Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Japan.
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Abe
authors.affiliation: Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan; Liver Cancer Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Japan.
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Wada
authors.affiliation: Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan; Liver Cancer Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Sakaue
authors.affiliation: Liver Cancer Division, Research Center for Innovative Cancer Therapy, Kurume University , Kurume, Japan.
authors.forename: Takato
authors.initials: T
authors.lastname: Ueno
authors.affiliation: Group of Translational Stem Cell Research, Department of Pharmacology, Osaka Medical College , Takatsuki, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Ii
authors.affiliation: Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University , Kyoto, Japan.
authors.forename: Cantas
authors.initials: C
authors.lastname: Alev
authors.affiliation: Group of Vascular Regeneration Research, Institute of Biomedical Research and Innovation , Kyoto, Japan.
authors.forename: Atsuhiko
authors.initials: A
authors.lastname: Kawamoto
authors.affiliation: Department of Regenerative Medicine Science, Tokai University School of Medicine , Isehara, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Asahara
authors.affiliation: Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine , Kurume, Japan.
authors.forename: Takuji
authors.initials: T
authors.lastname: Torimura