Rationale: Cortical bone stem cells (CBSCs) have been shown to reduce ventricular remodeling and improve cardiac function in a murine myocardial infarction (MI) model. These effects were superior to other stem cell types that have been used in recent early stage clinical trials. However, CBSC efficacy has not been tested in a preclinical large animal model using approaches that could be applied to patients.Objective:To determine if post-MI transendocardial injection of allogeneic CBSCs reduces pathological structural and functional remodeling and prevents the development of heart failure in a swine MI model.Methods and Results: Female Göttingen swine underwent left anterior descending coronary artery occlusion, followed by reperfusion (ischemia-reperfusion MI). Animals received, in a randomized, blinded manner, 1:1 ratio, CBSCs (n = 9) (2x10⁷ cells total) or placebo (vehicle; VEH, n = 9) through NOGA® guided transendocardial injections. 5-ethynyl-2'deoxyuridine (EdU), a thymidine analog, containing minipumps were inserted at the time of MI induction. At 72hrs (n=8) initial injury and cell retention were assessed. At 3 Months post-MI, cardiac structure and function was evaluated by serial echocardiography, and terminal invasive hemodynamics. CBSCs were present in the MI border zone and proliferating at 72hrs post-MI but had no effect on initial cardiac injury or structure. At 3 months, CBSC-treated hearts had significantly reduced scar size, smaller myocytes and increased myocyte nuclear density. Noninvasive echocardiographic measurements showed that left ventricular (LV) volumes and ejection fraction were significantly more preserved in CBSC-treated hearts and invasive hemodynamic measurements documented improved cardiac structure and functional reserve. The number of EdU⁺ cardiac myocytes was increased in CBSC- vs. VEH- treated animals.Conclusions: CBSC administration into the MI border zone reduces pathological cardiac structural and functional remodeling and improves LV functional reserve. These effects reduce those processes that can lead to heart failure with reduced ejection fraction (HFrEF). es that can lead to heart failure with reduced ejection fraction (HFrEF).

原理：皮质骨干细胞（CBSC）在鼠心肌梗死（MI）模型中可减少心室重构并改善心脏功能。这些效果优于最近的早期临床试验中使用的其他干细胞类型。但是，尚未使用可应用于患者的方法在临床前大型动物模型中测试CBSC功效。目的：确定在MI后心内膜异位注射的CBSCs注射是否能降低猪MI模型的病理结构和功能重塑，并预防心力衰竭的发展。方法和结果：雌性哥廷根猪左冠状动脉前降支闭塞，然后进行再灌注（缺血再灌注MI）。动物以随机，盲法接受1：1比例的CBSC（n = 9）（2x10 ⁷细胞总数）或安慰剂（载体； VEH，n = 9）通过NOGA®引导的心内膜注射。在MI诱导时插入含有微型泵的胸苷类似物5-乙炔基-2'脱氧尿苷（EdU）。在72小时（n ＝ 8）时，评估了初始损伤和细胞保留。在心梗后3个月，通过连续超声心动图和终末浸润性血流动力学评估心脏结构和功能。CBSC存在于MI边界区，并在MI后72小时扩散，但对最初的心脏损伤或结构没有影响。在3个月时，经CBSC处理的心脏的疤痕大小明显减小，心肌细胞更小，并且心肌细胞核密度增加。非侵入性超声心动图测量结果显示，在CBSC治疗的心脏中，左心室（LV）的体积和射血分数明显保留得更好，而侵入性血液动力学测量结果显示心脏结构和功能储备得到改善。教育学数CBSC处理组与VEH处理组相比，心肌细胞⁺增多。结论：将CBSC施用至MI边界区可减少病理性心脏结构和功能重塑，并改善LV功能储备。这些作用减少了那些可导致心力衰竭且射血分数降低（HFrEF）的过程。可能导致射血分数（HFrEF）降低的心力衰竭。