MSC-mediated mitochondrial transfer promotes metabolic reprograming in endothelial cells and vascular regeneration in ARDS

Mesenchymal stem cells (MSCs) are a potential therapy for acute respiratory distress syndrome (ARDS), but their mechanisms in repairing mitochondrial damage in ARDS endothelial cells remain unclear. We first examined MSCs’ mitochondrial transfer ability and mechanisms to mouse pulmonary microvascular endothelial cells (MPMECs) in ARDS. Then, we investigated how MSC-mediated mitochondrial transfer affects the repair of endothelial damage. Finally, we elucidated the mechanisms by which MSC-mediated mitochondrial transfer promotes vascular regeneration. Compared to mitochondrial-damaged MSCs, normal MSCs showed a significantly higher mitochondrial transfer rate to MPMECs, with increases of 41.68% in vitro (<i>P</i> &lt; 0.0001) and 10.50% in vivo (<i>P</i> = 0.0005). Furthermore, MSC-mediated mitochondrial transfer significantly reduced reactive oxygen species (<i>P</i> &lt; 0.05) and promoted proliferation (<i>P</i> &lt; 0.0001) in MPMECs. Finally, MSC-mediated mitochondrial transfer significantly increased the activity of the tricarboxylic acid (TCA) cycle (MD of CS mRNA: 23.76, <i>P</i> = 0.032), and further enhanced fatty acid synthesis (MD of FAS mRNA: 6.67, <i>P</i> = 0.0001), leading to a 6.7-fold increase in vascular endothelial growth factor release from MPMECs and promoted vascular regeneration in ARDS. MSC-mediated mitochondrial transfer to MPMECs activates the TCA cycle and fatty acid synthesis, promoting endothelial proliferation and pro-angiogenic factor release, thereby enhancing vascular regeneration in ARDS.