ICREC Research Program, Health Science Research Institute Germans Trias i Pujol (IGTP), Can Ruti Campus, Badalona, Spain.
Heart Institute (iCor), Cardiology Department, Germans Trias i Pujol University Hospital, Badalona, Spain.
Theranostics. 2022 Jun 6;12(10):4656-4670. doi: 10.7150/thno.72289. eCollection 2022.
Extracellular vesicles (EVs) from mesenchymal stromal cell (MSC) are a potential therapy for cardiac healing after myocardial infarction (MI). Nevertheless, neither their efficient administration nor therapeutic mechanisms are fully elucidated. Here, we evaluate the preclinical efficacy of a tissue engineering approach to locally deliver porcine cardiac adipose tissue MSC-EV (cATMSC-EV) in an acute MI pig model. After MI by permanent ligation of the coronary artery, pigs (n = 24) were randomized to Untreated or treated groups with a decellularised pericardial scaffold filled with peptide hydrogel and cATMSC-EV purified by size exclusion chromatography (EV-Treated group) or buffer (Control group), placed over the post-infarcted myocardium. After 30 days, cardiac MRI showed an improved cardiac function in EV-Treated animals, with significantly higher right ventricle ejection fraction (+20.8% in EV-Treated; = 0.026), and less ventricle dilatation, indicating less myocardial remodelling. Scar size was reduced, with less fibrosis in the distal myocardium (-42.6% Col I in EV-Treated Untreated; = 0.03), a 2-fold increase in vascular density (EV-Treated; = 0.019) and less CCL2 transcription in the infarct core. EV-treated animals had less macrophage infiltration in the infarct core (-31.7% of CD163 cells/field in EV-Treated; = 0.026), but 5.8 times more expressing anti-inflammatory CD73 ( = 0.015). Systemically, locally delivered cATMSC-EV also triggered a systemic effect, doubling the circulating IL-1ra ( = 0.01), and reducing the PBMC rush 2d post-MI, the TNFα and GM-CSF levels at 30d post-MI, and modulating the CD73 and CCR2 monocyte populations, related to immunomodulation and fibrosis modulation. These results highlight the potential of cATMSC-EV in modulating hallmarks of ischemic injury for cardiac repair after MI.
细胞外囊泡（EVs）来源于间充质基质细胞（MSC），是心肌梗死后心脏修复的一种有潜力的治疗方法。然而，其有效的给药途径和治疗机制尚未完全阐明。在这里，我们评估了一种组织工程方法的临床前疗效，该方法将猪心脏脂肪组织 MSC-EV（cATMSC-EV）局部递送至急性心肌梗死猪模型。通过冠状动脉永久性结扎造成心肌梗死后，将 24 只猪随机分为未治疗组或治疗组，治疗组使用脱细胞心包支架填充肽水凝胶，并通过分子筛色谱法纯化 cATMSC-EV（EV 治疗组）或缓冲液（对照组），然后将其放置在梗死心肌上。30 天后，心脏 MRI 显示 EV 治疗组动物心功能得到改善，右心室射血分数明显升高（EV 治疗组增加 20.8%； = 0.026），心室扩张减少，提示心肌重塑减少。疤痕面积减小，远段心肌纤维化减少（EV 治疗组 Collagen I 减少 42.6%； = 0.03），血管密度增加 2 倍（EV 治疗组； = 0.019），梗死核心 CCL2 转录减少。EV 治疗组梗死核心内巨噬细胞浸润减少（EV 治疗组 CD163 细胞/视野减少 31.7%； = 0.026），但表达抗炎性 CD73 的细胞增加 5.8 倍（ = 0.015）。在系统水平上，局部递送的 cATMSC-EV 也引发了全身性效应，使循环 IL-1ra 增加 2 倍（ = 0.01），并减少了心肌梗死后 2 天的 PBMC 浸润，减少了 30 天后的 TNFα 和 GM-CSF 水平，并调节了 CD73 和 CCR2 单核细胞群体，与免疫调节和纤维化调节有关。这些结果突出了 cATMSC-EV 调节缺血性损伤特征以促进心肌梗死后心脏修复的潜力。
