Mesenchymal stem cells rescue injured endothelial cells in an in vitro ischemia–reperfusion model via tunneling nanotube like structure-mediated mitochondrial transfer

• MSCs and HUVECs can exchange mitochondria via TNT-like structures.
• OGD/RO-induced mitochondrial transfer via TNT becomes frequent and unidirectional.
• The formation of TNT-like structures may represent a defense and rescue mechanism.
• MSCs rescue injured HUVECs via TNT-like structure-mediated mitochondrial transfer.

Mesenchymal stem cells can be used as a novel treatment of ischemic vascular disease; however, their therapeutic effect and mechanism of action require further evaluation. Mitochondrial dysfunction has core functions in ischemia–reperfusion injury of the microvascular network. A recent discovery has shown that intercellular communication using tunneling nanotubes can transfer mitochondria between adjacent cells. This study aimed to investigate the tunneling nanotube mechanisms that might be involved in stem cell-mediated mitochondrial rescue of injured vascular endothelial cells. Using laser scanning confocal microscopy, mitochondrial transfer via a tunneling nanotube-like structure was detected between mesenchymal stem cells and human umbilical vein endothelial cells. Oxygen glucose deprivation and reoxygenation were performed on human umbilical vein endothelial cells, which induced mitochondrial transfer through tunneling nanotube-like structures to become frequent and almost unidirectional from mesenchymal stem cells to injured endothelial cells, thereby resulting in the rescue of aerobic respiration and protection of endothelial cells from apoptosis. We found that the formation of tunneling nanotube-like structures might represent a defense and rescue mechanism through phosphatidylserines exposed on the surface of apoptotic endothelial cells and stem cell recognition. Our data provided evidence that stem cells can rescue damaged vascular endothelial cells through a mechanism that has not yet been identified.