Transplantation of mesenchymal stromal cell-derived mitochondria alleviates endothelial dysfunction in pre-clinical models of acute respiratory distress syndrome.

Summary

Human MSC-derived mitochondria were directly transferred to pulmonary microvascular endothelial cells exposed to LPS or ARDS patient plasma, reversing mitochondrial dysfunction and restoring barrier integrity without provoking inflammation. In LPS-challenged mice, intravenous MSC mitochondria reduced lung injury and alveolar inflammatory cell infiltration and increased VE-cadherin mRNA, indicating improved alveolar-capillary barrier function.

Key Findings

• LPS or ARDS patient plasma induced mitochondrial dysfunction and hyperpermeability in HPMEC.
• MSC-derived mitochondria were internalized by HPMEC without cytotoxic or pro-inflammatory effects, restoring mitochondrial function and barrier integrity at 24 h.
• In LPS-challenged mice, intravenous MSC mitochondria reduced lung injury and alveolar inflammatory cell infiltration and increased lung VE-cadherin mRNA.

Clinical Implications

Supports development of mitochondrial transplantation as an adjunctive therapy for ARDS, particularly for restoring endothelial barrier function. Patient selection by inflammatory phenotype, dosing, delivery route, and safety need evaluation before clinical translation.

Limitations

• Preclinical models without long-term safety, biodistribution, or dosing optimization data.
• Mechanistic pathways of mitochondrial uptake and integration were not deeply dissected.

Future Directions

Conduct large-animal studies and first-in-human feasibility trials; define dosing, delivery routes, and patient phenotypes most likely to benefit; elucidate uptake mechanisms and compare with MSCs/extracellular vesicles.