Stem Cell Therapy Unit, Jesus Uson Minimally Invasive Surgery Centre, Cáceres, Spain.
CIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain.
Stem Cell Rev Rep. 2020 Jun;16(3):612-625. doi: 10.1007/s12015-019-09926-y.
Acute myocardial infarction triggers a strong inflammatory response in the affected cardiac tissue. New therapeutic tools based on stem cell therapy may modulate the unbalanced inflammation in the damaged cardiac tissue, contributing to the resolution of this pathological condition. The main goal of this study was to analyze the immunomodulatory effects of cardiosphere-derived cells (CDCs) and their extracellular vesicles (EV-CDCs), delivered by intrapericardial administration in a clinically relevant animal model, during the initial pro-inflammatory phase of an induced myocardial infarction. This effect was assessed in peripheral blood and pericardial fluid leukocytes from infarcted animals. Additionally, cardiac functional parameters, troponin I, hematological and biochemical components were also analyzed to characterize myocardial infarction-induced changes, as well as the safety aspects of these procedures. Our preclinical study demonstrated a successful myocardial infarction induction in all animals, without any reported adverse effect related to the intrapericardial administration of CDCs or EV-CDCs. Significant changes were observed in biochemical and immunological parameters after myocardial infarction. The analysis of peripheral blood leukocytes revealed an increase of M2 monocytes in the EV-CDCs group, while no differences were reported in other lymphocyte subsets. Moreover, arginase-1 (M2-differentiation marker) was significantly increased in pericardial fluids 24 h after EV-CDCs administration. In summary, we demonstrate that, in our experimental conditions, intrapericardially administered EV-CDCs have an immunomodulatory effect on monocyte polarization, showing a beneficial effect for counteracting an unbalanced inflammatory reaction in the acute phase of myocardial infarction. These M2 monocytes have been defined as "pro-regenerative cells" with a pro-angiogenic and anti-inflammatory activity.
急性心肌梗死在受影响的心脏组织中引发强烈的炎症反应。基于干细胞治疗的新治疗工具可能会调节受损心脏组织中失衡的炎症，有助于解决这种病理状况。本研究的主要目的是分析心包内给药的心脏球源性细胞（cardiosphere-derived cells，CDCs）及其细胞外囊泡（extracellular vesicles，EV-CDCs）在诱导性心肌梗死的初始促炎阶段对炎症的免疫调节作用。在梗死动物的外周血和心包液白细胞中评估了这种作用。此外，还分析了心脏功能参数、肌钙蛋白 I、血液学和生化成分，以表征心肌梗死诱导的变化以及这些程序的安全性方面。我们的临床前研究表明，所有动物均成功诱导心肌梗死，心包内给予 CDCs 或 EV-CDCs 无任何报道的不良反应。心肌梗死后观察到生化和免疫学参数的显著变化。外周血白细胞分析显示 EV-CDC 组 M2 单核细胞增加，而其他淋巴细胞亚群无差异。此外，EV-CDC 给药 24 小时后心包液中精氨酸酶-1（M2 分化标志物）显著增加。总之，我们证明在我们的实验条件下，心包内给予 EV-CDCs 对单核细胞极化具有免疫调节作用，对心肌梗死后急性期失衡的炎症反应具有有益作用。这些 M2 单核细胞被定义为具有促血管生成和抗炎活性的“促再生细胞”。
