Transplantation Effectiveness of Induced Pluripotent Stem Cells Is Improved by a Fibrinogen Biomatrix in an Experimental Model of Ischemic Heart Failure.
Transplantation Effectiveness of Induced Pluripotent Stem Cells Is Improved by a Fibrinogen Biomatrix in an Experimental Model of Ischemic Heart Failure.
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DOI：
10.1089/ten.tea.2014.0537
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发表时间：
2015-04
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通讯作者：
S. Rojas;A. Martens;R. Zweigerdt;H. Baraki;Christian Rathert;Natalie Schecker;S. Rojas-Hernández;K. Schwanke;U. Martin;A. Haverich;I. Kutschka
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作者：
S. Rojas;A. Martens;R. Zweigerdt;H. Baraki;Christian Rathert;Natalie Schecker;S. Rojas-Hernández;K. Schwanke;U. Martin;A. Haverich;I. Kutschka
目的：本研究的目的是研究纤维蛋白原生物基质是否能提高诱导多能干细胞（iPSCs）在心肌梗死模型中的移植效果。背景：早期保留、移植和细胞增殖是心脏干细胞治疗成功的重要因素。常见的移植技术包括在水介质中定向注射细胞。然而，这种方法产生低保留率和可变的细胞生物分布，导致移植物减少，不能充分再生受损的心肌。生物相容性支架可以改善注射细胞的保留，从而改善心脏干细胞治疗。方法转染小鼠iPSCs，检测荧光素酶报告基因的表达。首先，体外实验比较纤维蛋白原和培养基中细胞活力。其次，在永久性左冠状动脉结扎后，通过直接注射将iPSCs移植到免疫缺陷小鼠缺血心肌中。细胞在培养基或纤维蛋白原中递送。随访包括生物发光成像评估移植物，磁共振成像评估心功能，组织学评估移植物大小，确定心肌瘢痕程度。结果体外实验显示，纤维蛋白原诱导的iPSCs在24 h后从6.4×10(3)±8.0×10(2)增殖到72 h后的2.1×10(4)±3.2×10(3)。对照组动物早期心肌细胞数量较低（23.7%±0.7%），右肺（46.3%±1.0%）和左肺（30.0%±0.6%）细胞大量堆积。当应用纤维蛋白原生物基质注射iPSCs时，心肌内细胞数量增加（66.3%±0.9%），并在实验过程中出现明显的移植物增殖。纤维蛋白原组左心室功能较高（42.9%±2.8%），梗死区再填充率也较高（66.9%±2.7%）。结论纤维蛋白原生物基质改善心肌iPSc保留，维持梗死心肌功能改善和细胞再填充。因此，纤维蛋白原可以被认为是一种理想的心内干细胞移植生物支架。
OBJECTIVES The aim of this study was to investigate whether a fibrinogen biomatrix improves the transplantation effectiveness of induced pluripotent stem cells (iPSCs) in a model of myocardial infarction. BACKGROUND Early retention, engraftment, and cell proliferation are important factors for successful cardiac stem cell therapy. Common transplantation techniques involve the direction injection of cells in aqueous media. However, this approach yields low retention and variable cell biodistribution, leading to reduced grafts that are unable to sufficiently regenerate damaged myocardium. Biologically compatible scaffolds that improve the retention of injected cells can improve cardiac stem cell therapy. METHODS Murine iPSCs were transfected for luciferase reporter gene expression. First, in vitro experiments were performed comparing cell viability in fibrinogen and medium. Second, iPSCs were transplanted intramyocardially by direct injection into ischemic myocardium of immunodeficient mice, following permanent left coronary artery ligation. Cells were delivered in medium or fibrinogen. Follow-up included graft assessment by bioluminescence imaging, the evaluation of cardiac function by magnetic resonance imaging, and histology to evaluate graft size and determine the extent of myocardial scarring. RESULTS In vitro experiments showed proliferation of iPSCs in fibrinogen from 6.4×10(3)±8.0×10(2) after 24 h to 2.1×10(4)±3.2×10(3) after 72 h. Early cardiac cell amount in control group animals was low (23.7%±0.7%) with massive cell accumulation in the right (46.3%±1.0%) and the left lung (30.0%±0.6%). When iPSCs were injected applying the fibrinogen biomatrix, intramyocardial cell amount was increased (66.3%±0.9%) with demonstrable graft proliferation over the experimental time course. Left ventricle-function was higher in the fibrinogen group (42.9%±2.8%), also showing a higher fraction of refilled infarcted-area (66.9%±2.7%). CONCLUSIONS The fibrinogen biomatrix improved cardiac iPSc retention, sustaining functional improvement and cellular refill of infarcted myocardium. Therefore, fibrinogen can be considered an ideal biological scaffold for intramyocardial stem cell transplantations.