MSC-Mediated Mitochondrial Transfer Promotes Metabolic Reprogramming in Endothelial Cells and Vascular Regeneration in ARDS

Background Acute Respiratory Distress Syndrome (ARDS) involves extensive pulmonary vascular endothelial injury. Mitochondrial damage plays a critical role in this endothelial injury. While mesenchymal stem cells (MSCs) are being explored as a cellular therapy for ARDS, their role in repairing mitochondrial damage in endothelial cells remains unclear. This study investigates the potential of MSCs to repair mitochondrial damage in ARDS lung endothelial cells through mitochondrial transfer and elucidates the underlying mechanisms. Methods This study established ARDS mouse models and cellular models of mitochondrial damage in pulmonary endothelial cells. Initially, we observed the ability and mechanisms of MSCs to transfer mitochondria to lung endothelial cells both in vivo and in vitro. Subsequently, we investigated how this mitochondrial transfer by MSCs affects the repair of mitochondrial and endothelial damage, as well as its impact on vascular regeneration in ARDS. Finally, we elucidated the mechanisms by which MSC-mediated mitochondrial transfer promotes vascular regeneration in ARDS. Various cell biology techniques, including flow cytometry, immunofluorescence staining, and confocal microscopy, were utilized for experimental observations. Results MSCs used tunneling nanotubes (TNTs) to transfer mitochondria to pulmonary endothelial cells. The endothelial cells internalized these mitochondria through dynamin-dependent clathrin-mediated endocytosis. The mitochondrial transfer increased mitochondrial complex I expression, reduced ROS production and apoptosis, and promoted cell proliferation in endothelial cells. The reparative effects of MSCs diminished when their mitochondrial transfer ability was inhibited. MSC-mediated mitochondrial transfer activated the tricarboxylic acid (TCA) cycle and citrate-dependent fatty acid synthesis in endothelial cells, leading to the release of pro-angiogenic factors and promoting vascular regeneration. Inhibiting TCA or fatty acid synthesis in endothelial cells significantly reduced MSC-promoted vascular regeneration. Conclusion MSCs transfer mitochondria to ARDS lung endothelial cells, activating the TCA cycle and fatty acid synthesis, which promotes endothelial cell proliferation and the release of pro-angiogenic factors, thereby enhancing vascular regeneration. These findings offer a promising therapeutic approach for repairing mitochondrial damage and promoting vascular regeneration in ARDS.