Combining cell therapy and extracorporeal membrane oxygenation for Acute Respiratory Distress Syndrome: Back to no future?

ABSTRACT

Introduction: After more than 50 years of research we are yet to develop an effective treatment for the Acute Respiratory Distress Syndrome (ARDS). This stands in contrast to the advances made in supportive care, a prime example of which is the maturation of Extracorporeal Membrane Oxygenation (ECMO). While technologies such as ECMO 'buy time' for recovery, the identification of a therapy remains crucial to improving outcomes. Recently, mesenchymal stem cells (MSCs) have shown promise as a novel treatment.1 Importantly, cell therapy may represent a means to overcome the hurdles associated with successful pharmacological intervention in ARDS. Little is known about the interaction between cell therapy and ECMO. This is a deficiency, given that those receiving ECMO for ARDS are among the most severely ill and therefore most likely to benefit. This programme of work was designed to close that gap. Objectives: Using a translational pipeline, our objective was to assess the safety and efficacy of MSCs during ECMO for ARDS. Methods: We employed several diverse methods to address our objectives, including an ex-vivo ECMO simulation, complex sheep models of ARDS and ARDS and venovenous ECMO, systematic review methodology, and unsupervised machine learning techniques. Results: In our ex-vivo model, we were the first to demonstrate potential harms associated with MSC therapy during ECMO.2 When 40 × 10∧6 clinical-grade human MSCs (Cynata Therapeutics Ltd., Australia) were added to fresh whole human blood and subjected to extracorporeal circulation using commercial components, oxygenator and pump performance was severely impaired within 4 hours. These experiments also demonstrated benefits associated with MSCs, including trends toward lower inflammatory cytokine concentrations and less neutrophil activation.3 To validate our findings, we sought to test hMSCs in a clinicallyrelevant sheep model. At the outset we undertook a systematic review of existing pre-clinical models of ARDS and ECMO.4 This has since produced an international collaborative effort to characterise pre-clinical models of ECMO across a range of indications. We subsequently described a 'double-hit' model of ARDS which combines oleic acid and intra-tracheal E. coli lipopolysaccharide. Using cluster analysis, we showed that this model shares qualitative similarities with the 'hypo-inflammatory' phenotype identified in clinical cohorts [Millar JE et al. Physiological Reports 2021. In Press]. Finally, in a 24-hour model, combining our novel injury method, VV-ECMO, and best practice ventilatory and supportive care, we performed a controlled trial of intra-tracheal hMSC therapy5 [Editorial Del Sorbo L, Fan E. AJRCCM 2020]. This study showed that hMSCs reduce histological evidence of lung injury and ameliorate shock. However, hMSC-mediated impairment of oxygenator function was evident again. Conclusion: This work addresses a gap in our understanding of cell therapy in critical illness. The findings are of direct clinical relevance, highlighting the potential harms of cell therapy during extracorporeal circulation. With a recent explosion in the number of registered clinical trials of MSCs for severe COVID-19 in mind, the use of MSCs during ECMO cannot be recommended.