BACKGROUND The combination of autologous mesenchymal stem cells (MSCs) and cardiac stem cells (CSCs) synergistically reduces scar size and improves cardiac function in ischemic cardiomyopathy. Whereas allogeneic (allo-)MSCs are immunoevasive, the capacity of CSCs to similarly elude the immune system remains controversial, potentially limiting the success of allogeneic cell combination therapy (ACCT). OBJECTIVES This study sought to test the hypothesis that ACCT synergistically promotes cardiac regeneration without provoking immunologic reactions. METHODS Göttingen swine with experimental ischemic cardiomyopathy were randomized to receive transendocardial injections of allo-MSCs + allo-CSCs (ACCT: 200 million MSCs/1 million CSCs, n = 7), 200 million allo-MSCs (n = 8), 1 million allo-CSCs (n = 4), or placebo (Plasma-Lyte A, n = 6). Swine were assessed by cardiac magnetic resonance imaging and pressure volume catheterization. Immune response was tested by histologic analyses. RESULTS Both ACCT and allo-MSCs reduced scar size by -11.1 ± 4.8% (p = 0.012) and -9.5 ± 4.8% (p = 0.047), respectively. Only ACCT, but not MSCs or CSCs, prevented ongoing negative remodeling by offsetting increases in chamber volumes. Importantly, ACCT exerted the greatest effect on systolic function, improving the end-systolic pressure-volume relation (+0.98 ± 0.41 mm Hg/ml; p = 0.016). The ACCT group had more phospho-histone H3+ (a marker of mitosis) cardiomyocytes (p = 0.04), and noncardiomyocytes (p = 0.0002) than did the placebo group in some regions of the heart. Inflammatory sites in ACCT and MSC-treated swine contained immunotolerant CD3+/CD25+/FoxP3+ regulatory T cells (p < 0.0001). Histologic analysis showed absent to low-grade inflammatory infiltrates without cardiomyocyte necrosis. CONCLUSIONS ACCT demonstrates synergistic effects to enhance cardiac regeneration and left ventricular functional recovery in a swine model of chronic ischemic cardiomyopathy without adverse immunologic reaction. Clinical translation to humans is warranted.

中文翻译：

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同种异体干细胞的组合促进心脏再生

背景自体间充质干细胞（MSCs）和心脏干细胞（CSCs）的组合协同减少瘢痕尺寸并改善缺血性心肌病的心脏功能。尽管同种异体 (allo-) MSCs 具有免疫逃避性，但 CSCs 类似地逃避免疫系统的能力仍然存在争议，这可能会限制同种异体细胞联合治疗 (ACCT) 的成功。目的 本研究试图检验 ACCT 协同促进心脏再生而不引起免疫反应的假设。方法 将患有实验性缺血性心肌病的哥廷根猪随机接受经心内膜注射 allo-MSCs + allo-CSCs（ACCT：2 亿​​个 MSCs/100 万个 CSCs，n = 7）、2 亿个 allo-MSCs（n = 8）、100 万个allo-CSC（n = 4）或安慰剂（Plasma-Lyte A，n = 6）。通过心脏磁共振成像和压力容积导管插入术对猪进行评估。通过组织学分析测试免疫反应。结果 ACCT 和异基因间充质干细胞使疤痕大小分别减少了 -11.1 ± 4.8% (p = 0.012) 和 -9.5 ± 4.8% (p = 0.047)。只有 ACCT，而不是 MSCs 或 CSCs，通过抵消腔室体积的增加来防止正在进行的负重塑。重要的是，ACCT 对收缩功能的影响最大，改善了收缩末期压力-容积关系（+0.98 ± 0.41 毫米汞柱/毫升；p = 0.016）。在心脏的某些区域，ACCT 组比安慰剂组有更多的磷酸组蛋白 H3+（有丝分裂的标志物）心肌细胞（p = 0.04）和非心肌细胞（p = 0.0002）。ACCT 和 MSC 处理的猪的炎症部位含有免疫耐受的 CD3+/CD25+/FoxP3+ 调节性 T 细胞（p < 0.0001）。组织学分析显示没有心肌细胞坏死的低度炎症浸润。结论 ACCT 在慢性缺血性心肌病猪模型中显示出增强心脏再生和左心室功能恢复的协同作用，且无不良免疫反应。临床转化为人类是有保证的。