López Esther, Marinaro Federica, de Pedro María de Los Ángeles, Sánchez-Margallo Francisco Miguel, Gómez-Serrano María, Ponath Viviane, Pogge von Strandmann Elke, Jorge Inmaculada, Vázquez Jesús, Fernández-Pereira Luis Miguel, Crisóstomo Verónica, Álvarez Verónica, Casado Javier G
Stem Cell Therapy Unit, Jesús Usón Minimally Invasive Surgery Centre, Cáceres, Spain.
CIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain.
Front Cell Dev Biol. 2020 Jun 9;8:321. doi: 10.3389/fcell.2020.00321. eCollection 2020.
Experimental data demonstrated that the regenerative potential and immunomodulatory capacity of cardiosphere-derived cells (CDCs) is mediated by paracrine mechanisms. In this process, extracellular vesicles derived from CDCs (EV-CDCs) are key mediators of their therapeutic effect. Considering the future applicability of these vesicles in human diseases, an accurate preclinical-to-clinical translation is needed, as well as an exhaustive molecular characterization of animal-derived therapeutic products. Based on that, the main goal of this study was to perform a comprehensive characterization of proteins and miRNAs in extracellular vesicles from porcine CDCs as a clinically relevant animal model. The analysis was performed by identification and quantification of proteins and miRNA expression profiles. Our results revealed the presence of clusters of immune-related and cardiac-related molecular biomarkers in EV-CDCs. Additionally, considering that priming stem cells with inflammatory stimuli may increase the therapeutic potential of released vesicles, here we studied the dynamic changes that occur in the extracellular vesicles from IFNγ-primed CDCs. These analyses detected statistically significant changes in several miRNAs and proteins. Notably, the increase in interleukin 6 (IL6) protein, as well as the increase in mir-125b (that targets IL6 receptor) was especially relevant. These results suggest a potential involvement of EV-CDCs in the regulation of the IL6/IL6R axis, with implications in inflammatory-mediated diseases.
实验数据表明，心脏球衍生细胞（CDCs）的再生潜能和免疫调节能力是由旁分泌机制介导的。在此过程中，源自CDCs的细胞外囊泡（EV-CDCs）是其治疗效果的关键介质。考虑到这些囊泡在人类疾病中的未来适用性，需要进行准确的临床前到临床的转化，以及对动物源治疗产品进行详尽的分子表征。基于此，本研究的主要目标是对猪CDCs细胞外囊泡中的蛋白质和微小RNA（miRNAs）进行全面表征，猪是一种与临床相关的动物模型。通过对蛋白质和miRNA表达谱的鉴定和定量进行分析。我们的结果揭示了EV-CDCs中存在免疫相关和心脏相关分子生物标志物簇。此外，考虑到用炎性刺激预处理干细胞可能会增加释放囊泡的治疗潜力，我们在此研究了经干扰素γ（IFNγ）预处理的CDCs细胞外囊泡中发生的动态变化。这些分析检测到几种miRNAs和蛋白质有统计学意义的变化。值得注意的是，白细胞介素6（IL6）蛋白的增加以及靶向IL6受体的mir-125b的增加尤为显著。这些结果表明EV-CDCs可能参与IL6/IL6R轴的调节，对炎症介导的疾病有影响。
