■外泌体治疗显示损伤后心脏修复的潜力。然而,半衰期短和缺乏明确的靶点等内在挑战阻碍了临床可行性。这里,我们报告了一种非侵入性和可重复的方法,用于在心肌梗死(MI)后通过吸入进行外泌体递送,我们称之为干细胞来源的外泌体雾化治疗(SCENT)。
■对干细胞衍生的外泌体进行大小分布和表面标记的表征。具有MI模型的C57BL/6小鼠通过雾化器连续7天接受外泌体吸入治疗。在SCENT后进行超声心动图检查以监测心功能,和组织学分析有助于研究心肌修复。对整个心脏进行单细胞RNA测序,以探索SCENT的作用机制。最后,可行性,功效,在猪MI模型中证明了SCENT的一般安全性,通过三维心脏磁共振成像促进。
■通过离体IVIS成像和荧光显微镜检测到SCENT后缺血心脏的外来体募集。在MI的小鼠模型中,SCENT通过改善左心室功能改善心脏修复,减少纤维化组织,促进心肌细胞增殖。使用SCENT后小鼠心脏的单细胞RNA测序的机制研究显示,内皮细胞(ECs)中Cd36的下调。在EC-Cd36fl/-条件敲除小鼠模型中,抑制ECs中的脂肪酸转运蛋白CD36,导致心脏葡萄糖利用的代偿性增加和更高的ATP生成,增强了心脏收缩力。在猪中,与对照组相比,在接受SCENT治疗的MI后第28天,心脏磁共振成像显示射血分数(Δ=11.66±5.12%)和缩短分数(Δ=5.72±2.29%)增强。伴随着梗死面积减小和心室壁增厚。
■在啮齿动物和猪模型中,我们的数据证明了可行性,功效,和SCENT治疗急性MI损伤的一般安全性,为临床研究奠定基础。此外,EC-Cd36fl/-小鼠模型提供了显示条件性EC-CD36敲除可以改善心脏损伤的第一个体内证据。我们的研究引入了一种非侵入性心脏病治疗方案,并确定了新的潜在治疗靶点。
UNASSIGNED: Exosome therapy shows potential for cardiac repair after injury. However, intrinsic challenges such as short half-life and lack of clear targets hinder the clinical feasibility. Here, we report a noninvasive and repeatable method for exosome delivery through
inhalation after myocardial infarction (MI), which we called stem cell-derived exosome nebulization therapy (SCENT).
UNASSIGNED: Stem cell-derived exosomes were characterized for size distribution and surface markers. C57BL/6 mice with MI model received exosome
inhalation treatment through a nebulizer for 7 consecutive days. Echocardiographies were performed to monitor cardiac function after SCENT, and histological analysis helped with the investigation of myocardial repair. Single-cell RNA sequencing of the whole heart was performed to explore the mechanism of action by SCENT. Last, the feasibility, efficacy, and general safety of SCENT were demonstrated in a swine model of MI, facilitated by 3-dimensional cardiac magnetic resonance imaging.
UNASSIGNED: Recruitment of exosomes to the ischemic heart after SCENT was detected by ex vivo IVIS imaging and fluorescence microscopy. In a mouse model of MI, SCENT ameliorated cardiac repair by improving left ventricular function, reducing fibrotic tissue, and promoting cardiomyocyte proliferation. Mechanistic studies using single-cell RNA sequencing of mouse heart after SCENT revealed a downregulation of Cd36 in endothelial cells (ECs). In an EC-Cd36fl/- conditional knockout mouse model, the inhibition of CD36, a fatty acid transporter in ECs, led to a compensatory increase in glucose utilization in the heart and higher ATP generation, which enhanced cardiac contractility. In pigs, cardiac magnetic resonance imaging showed an enhanced ejection fraction (Δ=11.66±5.12%) and fractional shortening (Δ=5.72±2.29%) at day 28 after MI by SCENT treatment compared with controls, along with reduced infarct size and thickened ventricular wall.
UNASSIGNED: In both rodent and swine models, our data proved the feasibility, efficacy, and general safety of SCENT treatment against acute MI injury, laying the groundwork for clinical investigation. Moreover, the EC-Cd36fl/- mouse model provides the first in vivo evidence showing that conditional EC-CD36 knockout can ameliorate cardiac injury. Our study introduces a noninvasive treatment option for heart disease and identifies new potential therapeutic targets.