title: Cardiosphere-derived cell sheet primed with hypoxia improves left ventricular function of chronically infarcted heart.
abstract: Cardiosphere-derived cells (CDCs) isolated from postnatal heart tissue are a convenient and efficientresource for the treatment of myocardial infarction. However, poor retention of CDCs in infarcted hearts often causes less than ideal therapeutic outcomes. Cell sheet technology has been developed as a means of permitting longer retention of graft cells, and this therapeutic strategy has opened new avenues of cell-based therapy for severe ischemic diseases. However, there is still scope for improvement before this treatment can be routinely applied in clinical settings. In this study, we investigated whether hypoxic preconditioning enhances the therapeutic efficacy of CDC monolayer sheets. To induce hypoxia priming, CDC monolayer sheets were placed in an incubator adjusted to 2% oxygen for 24 hours, and then preconditioned mouse CDC sheets were implanted into the infarcted heart of old myocardial infarction mouse models. Hypoxic preconditioning of CDC sheets remarkably increased the expression of vascular endothelial growth factor through the PI3-kinase/Akt signaling pathway. Implantation of preconditioned CDC sheets improved left ventricular function inchronically infarcted hearts and reduced fibrosis. The therapeutic efficacy of preconditioned CDC sheets was higher than the CDC sheets that were cultured under normaxia condition. These results suggest that hypoxic preconditioning augments the therapeutic angiogenic and anti-fibrotic activity of CDC sheets. A combination of cell sheets and hypoxic preconditioning offers an attractive therapeutic protocol for CDC transplantation into chronically infarcted hearts.
authors.affiliation: Department of Surgery and Clinical Science, Yamaguchi University Graduate School of MedicineUbe, Japan; Center for Regenerative Medicine, Yamaguchi University Graduate School of MedicineUbe, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Hosoyama
authors.affiliation: Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine Ube, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Samura
authors.affiliation: Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine Ube, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Kudo
authors.affiliation: Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine Ube, Japan.
authors.forename: Arata
authors.initials: A
authors.lastname: Nishimoto
authors.affiliation: Department of Surgery and Clinical Science, Yamaguchi University Graduate School of MedicineUbe, Japan; Center for Regenerative Medicine, Yamaguchi University Graduate School of MedicineUbe, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Ueno
authors.affiliation: Institute of Laboratory Animals, Yamaguchi University Graduate School of Medicine Ube, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Murata
authors.affiliation: Laboratory of Veterinary Pharmacology, Joint Faculty of Veterinary Medicine, Yamaguchi University Yamaguchi, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ohama
authors.affiliation: Laboratory of Veterinary Pharmacology, Joint Faculty of Veterinary Medicine, Yamaguchi University Yamaguchi, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Sato
authors.affiliation: Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine Ube, Japan.
authors.forename: Akihito
authors.initials: A
authors.lastname: Mikamo
authors.affiliation: Department of Surgery and Clinical Science, Yamaguchi University Graduate School of MedicineUbe, Japan; Graduate School of Health and Welfare, Yamaguchi Prefectural UniversityYamaguchi, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Yoshimura
authors.affiliation: Department of Stem Cell Biology, Atomic Bomb Disease Institute, Nagasaki University Nagasaki, Japan.
authors.forename: Tao-Sheng
authors.initials: TS
authors.lastname: Li
authors.affiliation: Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine Ube, Japan.
authors.forename: Kimikazu
authors.initials: K
authors.lastname: Hamano
keywords: Old myocardial infarction; cardiosphere-derived cells; cell sheet; cell-based therapy; hypoxic preconditioning