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

Background: 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.

Methods: 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.

Results: Compared to mitochondrial-damaged MSCs, normal MSCs showed a significantly higher mitochondrial transfer rate to MPMECs, with increases of 41.68% in vitro (P < 0.0001) and 10.50% in vivo (P = 0.0005). Furthermore, MSC-mediated mitochondrial transfer significantly reduced reactive oxygen species (P < 0.05) and promoted proliferation (P < 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, P = 0.032), and further enhanced fatty acid synthesis (MD of FAS mRNA: 6.67, P = 0.0001), leading to a 6.7-fold increase in vascular endothelial growth factor release from MPMECs and promoted vascular regeneration in ARDS.

Conclusion: 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.