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Pluripotent Stem Cell-Engineered Cell Sheets Re-Assembled with Defined Cardiovascular Populations Ameliorate Reduction in Infarct Heart Function Through Cardiomyocyte-Mediated Neovascularization.
MedLine Citation:
PMID:  22438013     Owner:  NLM     Status:  Publisher    
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 and mural cells can be systematically induced and purified. Combining this with cell-sheet technology, we generated cardiac tissue sheets re-assembled with defined cardiovascular populations. Here we show the potentials and mechanisms of cardiac tissue sheet transplantation in cardiac function after myocardial infarction. Transplantation of the cardiac tissue sheet to a rat myocardial infarction 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 LV 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 close 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 was achieved by sheet CMs. Endothelial and mural cells 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.
Hidetoshi Masumoto; Takehiko Matsuo; Kohei Yamamizu; Hideki Uosaki; Genta Narazaki; Shiori Katayama; Akira Marui; Tatsuya Shimizu; Tadashi Ikeda; Teruo Okano; Ryuzo Sakata; Jun K Yamashita
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-3-21
Journal Detail:
Title:  Stem cells (Dayton, Ohio)     Volume:  -     ISSN:  1549-4918     ISO Abbreviation:  -     Publication Date:  2012 Mar 
Date Detail:
Created Date:  2012-3-22     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9304532     Medline TA:  Stem Cells     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012 AlphaMed Press.
Laboratory of Stem Cell Differentiation, Stem Cell Research Center, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan; Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan; Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
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