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

Abstract

Background: Pulmonary endothelial dysfunction with increased capillary permeability is a key aspect in the pathogenesis of acute respiratory distress syndrome (ARDS). It has been demonstrated that mesenchymal stromal cells (MSC) can modulate host cells through mitochondrial transfer. Although mitochondrial transplantation is a promising treatment strategy for conditions underpinned by mitochondrial dysfunction, its therapeutic potential in ARDS has not been sufficiently investigated. Herein, we tested the potential of MSC mitochondrial transplantation to restore functionality of the pulmonary endothelium in pre-clinical models of ARDS.

Methods: Mitochondria (mt) derived from human bone-marrow MSC were isolated and immediately used for transplantation to primary human pulmonary microvascular endothelial cells (HPMEC) in the presence of Escherichia coli lipopolysaccharide (LPS) or plasma samples from ARDS patients classified into hypo- and hyper-inflammatory phenotypes. Mitochondrial function, inflammatory status, and barrier integrity of HPMEC were assessed at 24 h. LPS- challenged mice were treated with MSC-mt intravenously, and the severity of lung injury and inflammatory response were evaluated.

Results: Exposure to LPS or ARDS plasma induced endothelial hyperpermeability associated with mitochondrial dysfunction. MSC-mt were readily internalized by HPMEC without cytotoxicity or inflammatory response, mitigating mitochondrial dysfunction and restoring barrier integrity. In vivo, administration of MSC-mt alleviated lung injury, reduced inflammatory cell infiltration in the alveoli and increased VE-cadherin mRNA levels in the lung tissue, indicating restoration of the alveolar-capillary barrier integrity.

Conclusion: This study demonstrated MSC mitochondrial transplantation as a promising therapeutic approach for treatment of endothelial dysfunction in the context of acute inflammation. Further exploration of mitochondrial transplantation in ARDS is warranted.

Keywords: acute respiratory distress syndrome; mesenchymal stromal cells; mitochondrial dysfunction; mitochondrial transplantation; pulmonary endothelial barrier.