title: Pluripotent stem cell-engineered cell sheets reassembled with defined cardiovascular populations ameliorate reduction in infarct heart function through cardiomyocyte-mediated neovascularization.
abstract: Although stem cell therapy is a promising strategy for cardiac restoration, the heterogeneity of transplanted cells has been hampering the precise understanding of the cellular and molecular mechanisms. Previously, we established a cardiovascular cell differentiation system from mouse pluripotent stem cells, in which cardiomyocytes (CMs), endothelial cells (ECs), and mural cells (MCs) can be systematically induced and purified. Combining this with cell sheet technology, we generated cardiac tissue sheets reassembled with defined cardiovascular populations. Here, we show the potentials and mechanisms of cardiac tissue sheet transplantation in cardiac function after myocardial infarction (MI). Transplantation of the cardiac tissue sheet to a rat MI model showed significant and sustained improvement of systolic function accompanied by neovascularization. Reduction of the infarct wall thinning and fibrotic length indicated the attenuation of left ventricular remodeling. Cell tracing with species-specific fluorescent in situ hybridization after transplantation revealed a relatively early loss of transplanted cells and an increase in endogenous neovascularization in the proximity of the graft, suggesting an indirect angiogenic effect of cardiac tissue sheets rather than direct CM contributions. We prospectively dissected the functional mechanisms with cell type-controlled sheet analyses. Sheet CMs were the main source of vascular endothelial growth factor. Transplantation of sheets lacking CMs resulted in the disappearance of neovascularization and subsequent functional improvement, indicating that the beneficial effects of the sheet were achieved by sheet CMs. ECs and MCs enhanced the sheet functions and structural integration. Supplying CMs to ischemic regions with cellular interaction could be a strategic key in future cardiac cell therapy.
authors.affiliation: Department of Stem Cell Differentiation, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Masumoto
authors.forename: Takehiko
authors.initials: T
authors.lastname: Matsuo
authors.forename: Kohei
authors.initials: K
authors.lastname: Yamamizu
authors.forename: Hideki
authors.initials: H
authors.lastname: Uosaki
authors.forename: Genta
authors.initials: G
authors.lastname: Narazaki
authors.forename: Shiori
authors.initials: S
authors.lastname: Katayama
authors.forename: Akira
authors.initials: A
authors.lastname: Marui
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Shimizu
authors.forename: Tadashi
authors.initials: T
authors.lastname: Ikeda
authors.forename: Teruo
authors.initials: T
authors.lastname: Okano
authors.forename: Ryuzo
authors.initials: R
authors.lastname: Sakata
authors.forename: Jun K
authors.initials: JK
authors.lastname: Yamashita
mesh_terms: D000818:Animals; D003331:Coronary Vessels / Q000254:growth & development; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D009203:Myocardial Infarction / Q000473:pathology / Q000601:surgery*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology / Q000637:transplantation*; D018919:Neovascularization, Physiologic; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000502:physiology / Q000637:transplantation*; D011446:Prospective Studies; D051381:Rats; D011923:Rats, Nude; D033581:Stem Cell Transplantation / Q000379:methods; D023822:Tissue Engineering / Q000379:methods*