Mesenchymal stem cell treatment is associated with decreased perfusate concentration of interleukin-8 during ex vivo perfusion of donor lungs after 18-hour preservation

Abstract

Background: Ex vivo lung perfusion (EVLP) presents a unique therapeutic opportunity to administer mesenchymal stromal cells (MSCs) to lung grafts before transplantation. We sought to determine the optimal route and dose of viable human umbilical cord-derived MSCs to be delivered into ex vivo-perfused damaged swine lungs, and to measure their effect on concentration of growth factors and inflammatory mediators.

Methods: Pig lungs were conventionally retrieved, cold preserved for 18 hours, and perfused normothermically ex vivo for 12 hours. Physiologic data were recorded. No cells were administered to a control group of animals (n = 5). To examine the routes of administration, lungs were administered 50 × 10⁶ MSCs endobronchially (n = 3) or via the pulmonary artery (n = 3). To determine the doses, a dose-escalation study was performed wherein lungs were administered 50 × 10⁶ (n = 3), 150 × 10⁶ (n = 5) and 300 × 10⁶ (n = 3) MSCs via the pulmonary artery. Concentrations of human growth factors and pig cytokines were measured in lung biopsies and perfusate.

Results: Intravascular administration of 50 × 10⁶ MSCs was associated with significant and sustained retention of MSCs in lung parenchyma, whereas intrabronchial administration was not. Intravascular administration of 150 × 10⁶ MSCs was the optimal tolerated dose and was associated with increased concentrations of human vascular endothelial growth factor (VEGF) in lung biopsies and decreased concentrations of pig interleukin-8 (IL-8) in the perfusate during 12 hours of EVLP.

Conclusions: Intravascular delivery of 150 × 10⁶ MSCs showed preferred outcome compared with intrabronchial delivery to damaged lungs perfused ex vivo. The method was well tolerated and associated with an increased concentration of human VEGF in the lung tissue and a decreased concentration of pig IL-8 in the perfusate.

Keywords: cell therapy; ex vivo lung perfusion; lung preservation; lung transplantation; mesenchymal stromal cells.