Mitochondrial dysfunction in Acute Respiratory Distress Syndrome and therapeutic mechanism of mesenchymal stromal cell derived extracellular vesicles

The role of Biogenesis in modulation of HPMEC was studied using specific pharmacological inhibitor (SR18292). Knockdown of protein GPS2 expression in EVs was performed by siRNA treatment of MSCs.<br><br>Transcriptomic analysis of the lung tissue revealed LPS significantly inhibited key pathways of mitochondrial biogenesis, compared to healthy controls. Vascular endothelial cells was the largest population identified by unsupervised clustering, within this population expression of the master regulator of mitochondrial biogenesis (PGC-1a) as well as downstream mediators (TFAM and PPARG) was decreased by LPS and restored with control EVs but not with RhoEVs.

In vitro, LPS reduced protein expression of PGC-1a and downstream mediators in HPMECs, which were restored by control EVs but not by RhoEVs. SR18292 impeded HPMEC ability to maintain barrier integrity. GPS2 silenced EVs are unable to restore LPS induced barrier integrity.<br><br>Mitochondrial homeostasis is disrupted in acute lung injury in vivo.

EV mitochondrial transfer is critical for restoration of mitochondrial biogenesis in pulmonary endothelial cells in vivo and in vitro. PGC1a is important regulator of endothelial lung barrier integrity and mediator of EV effect.<br><br><i>Thesis is embargoed until 31st Jul 2028</i>