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Differentiation, survival, and function of embryonic stem cell derived endothelial cells for ischemic heart disease

lizongjin 添加于 2012-4-1 19:49 | 1155 次阅读 | 0 个评论

作者
Li Z, Wu JC, Sheikh AY, Kraft D, Cao F, Xie X, Patel M, Gambhir SS, Robbins RC, Cooke JP, Wu JC
摘要
BACKGROUND: Embryonic stem (ES) cells are distinguished by their capacity for self-renewal and pluripotency. Here we characterize the differentiation of ES cell-derived endothelial cells (ESC-ECs), use molecular imaging techniques to examine their survival in vivo, and determine the therapeutic efficacy of ESC-ECs for restoration of cardiac function after ischemic injury. METHODS AND RESULTS: Murine ES cells were transfected with a construct composed of a vascular endothelial cadherin promoter driving enhanced green fluorescence protein (pVE-cadherin-eGFP). Differentiation of ES cells to ECs was detected by FACS analysis using Flk-1 (early EC marker at day 4) and VE-cadherin (late EC marker at day 8). After isolation, these ESC-ECs express endothelial cell markers similar to adult mouse lung endothelial cells, form vascular-like channels, and incorporate DiI-labeled acetylated low-density lipoprotein (DiI-Ac-LDL). For in vivo imaging, ES cells were transduced with an ubiquitin promoter driving firefly luciferase and monomeric red fluorescence protein (pUb-Fluc-mRFP). A robust correlation exists between Fluc signals and cell numbers by ex vivo imaging analysis (R2=0.98) and by in vitro enzyme assay (R2=0.94). Afterward, 5x10(5) ESC-ECs or PBS (as control) was injected into the hearts of mice undergoing LAD ligation (n=15 per group). Bioluminescence imaging showed longitudinal survival of transplanted ESC-ECs for approximately 8 weeks. Echocardiogram demonstrated significant functional improvement in the ESC-EC group compared with control (P=0.04). Finally, postmortem analysis confirmed increased presence of small capillaries and venules in the infarcted zones by CD31 staining. CONCLUSIONS: This is the first study to track the fate and function of transplanted ESC-ECs in the heart. With further validation, these ESC-ECs could become a valuable source of cell therapy for induction of angiogenesis in the treatment of myocardial ischemia.
详细资料
- 关键词: Animals; *Cell Differentiation/physiology; Cell Line; Cell Survival/physiology; Embryonic Stem Cells/*cytology/physiology/transplantation; Endothelial Cells/*cytology/physiology/transplantation; Endothelium, Vascular/*cytology/physiology/transplantation; Female; Mice; Myocardial Ischemia/pathology/*surgery; Stem Cell Transplantation/*methods
- 文献种类:期刊
- 期刊名称: Circulation
- 期刊缩写: Circulation
- 期卷页: 2007年第116卷第11 Suppl期 I46-54页
- 地址: Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305, USA
- ISBN: 0009-7322
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