Riegler Johannes, Gillich Astrid, Shen Qi, Gold Joseph D, Wu Joseph C
From the Department of Medicine, Division of Cardiology and Department of Radiology, Stanford Cardiovascular Institute (J.R., Q.S., J.C.W.), Department of Biochemistry (A.G.), and Department of Cardiothoracic Surgery (J.D.G.), Stanford University School of Medicine, CA.
Circulation. 2014 Sep 9;130(11 Suppl 1):S77-86. doi: 10.1161/CIRCULATIONAHA.113.007920.
Cell therapies offer the potential to improve cardiac function after myocardial infarction. Although injection of single-cell suspensions has proven safe, cell retention and survival rates are low. Tissue-engineered grafts allow cell delivery with minimal initial cell loss and mechanical support to the heart. However, graft performance cannot be easily compared, and optimal construct thickness, vascularization, and survival kinetics are unknown.
Cardiac tissue slices (CTS) were generated by sectioning mouse hearts (n=40) expressing firefly luciferase and green fluorescent protein into slices of defined size and thickness using a vibrating blade microtome. Bioluminescence imaging of CTS transplanted onto hearts of immunodeficient mice demonstrated survival of ≤30% of transplanted cells. Cardiac slice perfusion was re-established within 3 days, likely through anastomosis of pre-existing vessels with the host vasculature and invasion of vessels from the host. Immunofluorescence showed a peak in cell death 3 days after transplantation and a gradual decline thereafter. MRI revealed preservation of contractile function and an improved ejection fraction 1 month after transplantation of CTS (28±2% CTS versus 22±2% control; P=0.05). Importantly, this effect was specific to CTS because transplantation of skeletal muscle tissue slices led to faster dilative remodeling and higher animal mortality.
In summary, this is the first study to use CTS as a benchmark to validate and model tissue-engineered graft studies. CTS transplantation improved cell survival, established reperfusion, and enhanced cardiac function after myocardial infarction. These findings also confirm that dilative remodeling can be attenuated by topical transplantation of CTS but not skeletal muscle tissue grafts.
细胞疗法为改善心肌梗死后的心功能提供了可能。尽管注射单细胞悬液已被证明是安全的，但细胞保留率和存活率较低。组织工程移植物能够在初始细胞损失最小的情况下实现细胞递送，并为心脏提供机械支撑。然而，移植物的性能不易比较，最佳构建厚度、血管化程度和存活动力学尚不清楚。
将表达萤火虫荧光素酶和绿色荧光蛋白的小鼠心脏（n = 40）用振动切片机切成特定大小和厚度的切片，制成心脏组织切片（CTS）。将CTS移植到免疫缺陷小鼠心脏上后进行生物发光成像，结果显示移植细胞的存活率≤30%。移植后3天内重新建立了心脏切片灌注，这可能是通过既有血管与宿主脉管系统的吻合以及宿主血管的侵入实现的。免疫荧光显示移植后3天细胞死亡达到峰值，此后逐渐下降。磁共振成像显示，移植CTS 1个月后收缩功能得以保留，射血分数有所改善（CTS组为28±2%，对照组为22±2%；P = 0.05）；重要的是，这种效果是CTS特有的，因为移植骨骼肌组织切片会导致更快的扩张性重塑和更高的动物死亡率。
总之，这是第一项将CTS用作基准来验证和模拟组织工程移植物研究的研究。CTS移植提高了细胞存活率、建立了再灌注并增强了心肌梗死后的心功能。这些发现还证实，通过局部移植CTS而非骨骼肌组织移植物可减轻扩张性重塑。
