Platelets are known to enhance the wound-healing activity of mesenchymal stem cells (MSCs). However, the mechanism by which platelets improve the therapeutic potential of MSCs has not been elucidated. Here, we provide evidence that, upon their activation, platelets transfer respiratory-competent mitochondria to MSCs primarily via dynamin-dependent clathrin-mediated endocytosis. We found that this process enhances the therapeutic efficacy of MSCs following their engraftment in several mouse models of tissue injury, including full-thickness cutaneous wound and dystrophic skeletal muscle. By combining in vitro and in vivo experiments, we demonstrate that platelet-derived mitochondria promote the pro-angiogenic activity of MSCs via their metabolic remodeling. Notably, we show that activation of the de novo fatty acid synthesis pathway is required for increased secretion of pro-angiogenic factors by platelet-preconditioned MSCs. These results reveal a new mechanism by which platelets potentiate MSC properties and underline the importance of testing platelet mitochondria quality prior to their clinical use.

众所周知，血小板可以增强间充质干细胞 (MSC) 的伤口愈合活性。然而，血小板提高MSCs治疗潜力的机制尚未阐明。在这里，我们提供的证据表明，血小板在活化后，主要通过动力蛋白依赖性网格蛋白介导的内吞作用将具有呼吸功能的线粒体转移到 MSC。我们发现，在植入多种组织损伤小鼠模型（包括全层皮肤伤口和营养不良的骨骼肌）后，该过程增强了 MSCs 的治疗效果。通过结合体外和体内在实验中，我们证明血小板衍生的线粒体通过其代谢重塑促进 MSC 的促血管生成活性。值得注意的是，我们表明，血小板预处理的 MSCs 增加促血管生成因子的分泌需要激活从头脂肪酸合成途径。这些结果揭示了血小板增强 MSC 特性的新机制，并强调了在临床使用之前测试血小板线粒体质量的重要性。