Pluripotent Stem Cell-Engineered Cell Sheets Reassembled with Defined Cardiovascular Populations Ameliorate Reduction in Infarct Heart Function Through Cardiomyocyte-Mediated Neovascularization
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 st...
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Published in | Stem cells (Dayton, Ohio) Vol. 30; no. 6; pp. 1196 - 1205 |
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Main Authors | , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Hoboken
Wiley Subscription Services, Inc., A Wiley Company
01.06.2012
Oxford University Press |
Subjects | |
Online Access | Get full text |
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Summary: | 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. STEM CELLS2012;30:1196–1205 |
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Bibliography: | istex:C1C79BC7C98D7C2EC2BF886A1EF714C8AC2643A4 Realization of Regenerative Medicine Ministry of Education, Culture, Sports, Science, and Technology, Japan fellowship from the Japan Society Promotion of Science New Energy Industrial Development Organization of Japan Author contributions: H.M.: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript; T.M., K.Y., and H.U.: collection and/or assembly of data and final approval of manuscript; G.N.: provision of study material or patients and final approval of manuscript; S.K.: manuscript writing and final approval of manuscript; A.M.: conception and design, financial support, and final approval of manuscript; T.S.: conception and design, provision of study material or patients, and final approval of manuscript; T.I.: conception and design, financial support, and final approval of manuscript; T.O.: conception and design and final approval of manuscript; R.S.: conception and design, financial support, and final approval of manuscript; J.K.Y.: conception and design, financial support, data analysis and interpretation, manuscript writing, and final approval of manuscript. Invited Research Project of Transnational Research Center, Kyoto University Hospital Disclosure of potential conflicts of interest is found at the end of this article. ArticleID:STEM1089 Japan Heart Foundation Young Investigator's Research Grant ark:/67375/WNG-BGPKNZJ8-5 Ministry of Health, Labor, and Welfare, Japan First published online in S C XPRESS E March 21, 2012. Telephone: +81‐75‐751‐3853; Fax: +81‐75‐751‐4824 TEM ELLS ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1066-5099 1549-4918 |
DOI: | 10.1002/stem.1089 |