Pluripotent Stem Cell-Engineered Cell Sheets Reassembled with Defined Cardiovascular Populations Ameliorate Reduction in Infarct Heart Function Through Cardiomyocyte-Mediated Neovascularization

被引：127

作者：

Masumoto, Hidetoshi ^{[2
,3
]}

Matsuo, Takehiko ^{[2
,3
]}

Yamamizu, Kohei ^{[2
]}

Uosaki, Hideki ^{[2
]}

Narazaki, Genta ^{[2
]}

Katayama, Shiori ^{[2
]}

Marui, Akira ^{[3
,4
]}

Shimizu, Tatsuya ^{[5
]}

Ikeda, Tadashi ^{[3
]}

Okano, Teruo ^{[5
]}

Sakata, Ryuzo ^{[3
]}

Yamashita, Jun K. ^{[1
,2
]}

机构：

[1] Kyoto Univ, Dept Stem Cell Differentiat, Inst Frontier Med Sci, Grad Sch Med,Sakyo Ku, Kyoto 6068507, Japan

[2] Kyoto Univ, Dept Cell Growth & Differentiat, Grad Sch Med, Ctr iPS Cell Res & Applicat CiRA, Kyoto 6068507, Japan

[3] Kyoto Univ, Dept Cardiovasc Surg, Grad Sch Med, Kyoto 6068507, Japan

[4] Kyoto Univ Hosp, Translat Res Ctr, Dept Expt Therapeut, Kyoto 606, Japan

[5] Tokyo Womens Med Univ, Inst Adv Biomed Engn & Sci, Tokyo, Japan

来源：

STEM CELLS | 2012年 / 30卷 / 06期

基金：

日本学术振兴会;

关键词：

Pluripotent stem cells; Tissue engineering; Myocardial infarction; Ventricular remodeling; ACUTE MYOCARDIAL-INFARCTION; BONE-MARROW-CELLS; LEFT-VENTRICULAR DYSFUNCTION; IMPROVES CARDIAC-FUNCTION; MYOBLAST TRANSPLANTATION; INTRACORONARY INFUSION; VASCULAR PROGENITORS; ENDOTHELIAL-CELLS; MONONUCLEAR-CELLS; IMPROVED SURVIVAL;

D O I：

10.1002/stem.1089

中图分类号：

Q813 [细胞工程];

学科分类号：

100113 [医学细胞生物学];

摘要：

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;30:11961205

引用

页码：1196 / 1205

页数：10

共 62 条

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