Combined Mesenchymal Stromal Cell Therapy and ECMO in ARDS: A Controlled Experimental Study in Sheep

Am J Respir Crit Care Med. 2020 Apr 15. doi: 10.1164/rccm.201911-2143OC. Online ahead of print.

Abstract

Rationale: Mesenchymal stromal cell therapy is a promising intervention for ARDS, although trials to date have not investigated its use alongside ECMO. Recent pre-clinical studies have suggested that combining these interventions may attenuate the efficacy of ECMO.

Objectives: To determine the safety and efficacy of mesenchymal stromal cell therapy in a model of ARDS and ECMO.

Methods: ARDS was induced in 14 sheep, after which they were established on veno-venous ECMO. Subsequently, they received either, endobronchial iPSC-derived human MSCs (hMSCs, n=7) or cell-free carrier vehicle (Vehicle control, n=7). During ECMO, a low tidal volume ventilation strategy was employed in addition to protocolized hemodynamic support. Animals were monitored and supported for 24 hours. Lung tissue, bronchoalveolar fluid, and plasma were analysed, in addition to continuous respiratory and hemodynamic monitoring.

Measurements and main results: The administration of hMSCs did not improve oxygenation (PaO2/FiO2 mean difference -146 mmHg, p = 0.076) or pulmonary function. However, histological evidence of lung injury (Lung Injury Score mean difference -0.07, p = 0.04) and BAL IL-8 were reduced. In addition, hMSC treated animals had a significantly lower cumulative requirement for vasopressor. Despite endobronchial administration, animals treated with hMSCs had a significant elevation in trans-membrane oxygenator pressure gradients. This was accompanied by more pulmonary artery thromboses and adherent hMSCs found on explanted oxygenator fibers.

Conclusions: Endobronchial hMSC therapy in an ovine model of ARDS and ECMO can impair membrane oxygenator function and does not improve oxygenation. These data do not recommend the safe use of hMSCs during VV-ECMO.

Keywords: Acute Respiratory Distress Syndrome; Extracorporeal membrane oxygenation; Mesenchymal stromal cells; Models, Animal.