Micro RNA based MSC EV engineering: Targeting the BMP2 cascade for bone repair.
Micro RNA based MSC EV engineering: Targeting the BMP2 cascade for bone repair.
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DOI：
10.3389/fcell.2023.1127594
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发表时间：
2023
影响因子：
5.5
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中科院分区：
文献类型：
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间充质干细胞衍生的细胞外囊泡（MSC EV）具有优异的免疫调节和治疗特性。虽然有益，但从转化的角度来看，需要具有一致功能和目标特异性的细胞外囊泡才能实现精准医学和组织工程的目标。先前的研究已发现间充质干细胞来源的细胞外囊泡的 miRNA 组成对细胞外囊泡的功能有显着贡献。在这项研究中，我们假设使用基于 miRNA 的细胞外囊泡工程方法可以使间充质干细胞衍生的细胞外囊泡功能具有途径特异性。为了检验这一假设，我们利用骨修复作为模型系统，并将 BMP2 信号级联作为目标途径。我们对间充质干细胞胞外囊泡进行了改造，使其具有更高水平的 miR-424（BMP2 信号级联的增强剂）。我们评估了这些细胞外囊泡的物理和功能特征及其在体外触发幼稚间充质干细胞成骨分化和促进体内骨修复的增强能力。结果表明，工程化的细胞外囊泡保留了其细胞外囊泡特征和内吞功能，并通过激活 SMAD1/5/8 磷酸化和体外间充质干细胞分化来增强骨诱导功能，并增强体内骨修复。此外，间充质干细胞来源的细胞外囊泡的固有免疫调节特性保持不变。这些结果可作为再生医学应用中基于 miRNA 的细胞外囊泡工程方法的概念验证。
Mesenchymal stem cell derived extracellular vesicles (MSC EVs) possess excellent immunomodulatory and therapeutic properties. While beneficial, from a translational perspective, extracellular vesicles with consistent functionality and target specificity are required to achieve the goals of precision medicine and tissue engineering. Prior research has identified that the miRNA composition of mesenchymal stem cell derived extracellular vesicles contributes significantly towards extracellular vesicles functionality. In this study, we hypothesized that mesenchymal stem cell derived extracellular vesicle functionality can be rendered pathway-specific using a miRNA-based extracellular vesicles engineering approach. To test this hypothesis, we utilized bone repair as a model system and the BMP2 signaling cascade as the targeted pathway. We engineered mesenchymal stem cell extracellular vesicles to possess increased levels of miR-424, a potentiator of the BMP2 signaling cascade. We evaluated the physical and functional characteristics of these extracellular vesicles and their enhanced ability to trigger the osteogenic differentiation of naïve mesenchymal stem cell in vitro and facilitate bone repair in vivo. Results indicated that the engineered extracellular vesicles retained their extracellular vesicles characteristics and endocytic functionality and demonstrated enhanced osteoinductive function by activating SMAD1/5/8 phosphorylation and mesenchymal stem cell differentiation in vitro and enhanced bone repair in vivo. Furthermore, the inherent immunomodulatory properties of the mesenchymal stem cell derived extracellular vesicles remained unaltered. These results serve as a proof-of-concept for miRNA-based extracellular vesicles engineering approaches for regenerative medicine applications.