Platelets Facilitate the Wound-Healing Capability of Mesenchymal Stem Cells by Mitochondrial Transfer and Metabolic Reprogramming

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. [Display omitted] •Platelets transfer respiratory-competent mitochondria to MSCs•Such transfers improve the wound-healing capacity of MSCs via increased angiogenesis•Such transfers activate de novo fatty acid synthesis in MSCs•Such activation in MSCs triggers the secretion of pro-angiogenic factors Levoux et al., report a novel mechanism by which platelets improve the regenerative capacity of mesenchymal stem cells (MSCs). They discovered that activated platelets release respiratory-competent mitochondria to MSCs and that this process improves the MSC pro-angiogenic function through the elevation of the cytosolic citrate level and stimulation of fatty acid synthesis.