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

on behalf of the Combining Extracorporeal Life Support and Cell Therapy in Critical Illness (CELTIC) investigators. This study, employing a 24-hour, large animal model of ARDS and ECMO, examined the safety and efficacy of MSC therapy. We found that endobronchially administered MSCs adhere to, and impair, membrane oxygenators in-vivo . MSCs did not improve oxygenation or other ventilatory parameters but did reduce the severity of histological evidence of lung injury. Our data also suggest that MSCs may reduce circulatory shock associated with ARDS. There were no adverse effects of MSC administration on renal or liver function. 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. Mitochondrial Transfer via Tunneling Nanotubes is an Important Mechanism by Which Mesenchymal Stem Cells Enhance Macrophage

[1]  Do Wan Kim,et al.  Viability of Mesenchymal Stem Cells in an Ex Vivo Circulation System , 2020, ASAIO journal.

[2]  J. Fraser,et al.  Combined MSC therapy and ECMO in experimental ARDS , 2020 .

[3]  J. Merlin,et al.  Bone marrow vs Wharton’s jelly mesenchymal stem cells in experimental sepsis: a comparative study , 2019, Stem Cell Research & Therapy.

[4]  J. Marshall,et al.  Effects of Mesenchymal Stem Cell Treatment on Systemic Cytokine Levels in a Phase 1 Dose Escalation Safety Trial of Septic Shock Patients* , 2019, Critical care medicine.

[5]  J. Laffey,et al.  Identification and Modulation of Microenvironment Is Crucial for Effective Mesenchymal Stromal Cell Therapy in Acute Lung Injury. , 2019, American journal of respiratory and critical care medicine.

[6]  Gavin D Perkins,et al.  Guidelines on the management of acute respiratory distress syndrome , 2019, BMJ Open Respiratory Research.

[7]  J. Fraser,et al.  Extracorporeal membrane oxygenation (ECMO) and the acute respiratory distress syndrome (ARDS): a systematic review of pre-clinical models , 2019, Intensive Care Medicine Experimental.

[8]  M. Exline,et al.  Treatment with allogeneic mesenchymal stromal cells for moderate to severe acute respiratory distress syndrome (START study): a randomised phase 2a safety trial. , 2019, The Lancet. Respiratory medicine.

[9]  B. Lopresti,et al.  Cell therapy for ARDS: efficacy of endobronchial versus intravenous administration and biodistribution of MAPCs in a large animal model , 2019, BMJ Open Respiratory Research.

[10]  T. van der Poll,et al.  Intravenous Infusion of Human Adipose Mesenchymal Stem Cells Modifies the Host Response to Lipopolysaccharide in Humans: A Randomized, Single‐Blind, Parallel Group, Placebo Controlled Trial , 2018, Stem cells.

[11]  L. Reppel,et al.  Clinical-grade mesenchymal stem cells derived from umbilical cord improve septic shock in pigs , 2018, Intensive Care Medicine Experimental.

[12]  K. Peters,et al.  Adipose-derived mesenchymal stem cells release microvesicles with procoagulant activity. , 2018, The international journal of biochemistry & cell biology.

[13]  B. Ko,et al.  Airway Delivery of Bone Marrow–Derived Mesenchymal Stem Cells Reverses Bronchopulmonary Dysplasia Superimposed with Acute Respiratory Distress Syndrome in an Infant , 2018, Cell medicine.

[14]  D. Brodie,et al.  Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome , 2018, The New England journal of medicine.

[15]  J. Fraser,et al.  Administration of mesenchymal stem cells during ECMO results in a rapid decline in oxygenator performance , 2018, Thorax.

[16]  J. L. Rosa,et al.  Mesenchymal stem cells improves survival in LPS‐induced acute lung injury acting through inhibition of NETs formation , 2017, Journal of cellular physiology.

[17]  M. Amato,et al.  Effect of Lung Recruitment and Titrated Positive End-Expiratory Pressure (PEEP) vs Low PEEP on Mortality in Patients With Acute Respiratory Distress Syndrome: A Randomized Clinical Trial , 2017, JAMA.

[18]  C. Bermudez,et al.  The Use of GMP-Produced Bone Marrow Derived Stem Cells in Combination with Extra Corporeal Membrane Oxygenation in ARDS -An Animal Model. , 2017, ASAIO journal.

[19]  J. Fraser,et al.  The inflammatory response to extracorporeal membrane oxygenation (ECMO): a review of the pathophysiology , 2016, Critical Care.

[20]  J. Marshall,et al.  Evaluating mesenchymal stem cell therapy for sepsis with preclinical meta-analyses prior to initiating a first-in-human trial , 2016, eLife.

[21]  C. Shimbori,et al.  Human mesenchymal stem cells attenuate early damage in a ventilated pig model of acute lung injury. , 2016, Stem cell research.

[22]  M. Matthay,et al.  Mitochondrial Transfer via Tunneling Nanotubes is an Important Mechanism by Which Mesenchymal Stem Cells Enhance Macrophage Phagocytosis in the In Vitro and In Vivo Models of ARDS , 2016, Stem cells.

[23]  M. Balaan,et al.  Acute Respiratory Distress Syndrome , 2016, Critical care nursing quarterly.

[24]  M. Rudnicki,et al.  Efficacy of Mesenchymal Stromal Cell Therapy for Acute Lung Injury in Preclinical Animal Models: A Systematic Review , 2016, PloS one.

[25]  E. Parovichnikova,et al.  The Results of the Russian Clinical Trial of Mesenchymal Stromal Cells (MSCs) in Severe Neutropenic Patients (pts) with Septic Shock (SS) (RUMCESS trial) , 2015 .

[26]  F. Barry,et al.  Bone Marrow‐Derived Mesenchymal Stem Cells Have Innate Procoagulant Activity and Cause Microvascular Obstruction Following Intracoronary Delivery: Amelioration by Antithrombin Therapy , 2015, Stem cells.

[27]  R. Sandberg,et al.  In Vivo Effects of Mesenchymal Stromal Cells in Two Patients With Severe Acute Respiratory Distress Syndrome , 2015, Stem cells translational medicine.

[28]  J. Fraser,et al.  Mesenchymal stromal cells and the acute respiratory distress syndrome (ARDS): challenges for clinical application , 2015, Thorax.

[29]  J. Laffey,et al.  Human mesenchymal stromal cells decrease the severity of acute lung injury induced by E. coli in the rat , 2015, Thorax.

[30]  E. Washington,et al.  Effect of Mesenchymal Precursor Cells on the Systemic Inflammatory Response and Endothelial Dysfunction in an Ovine Model of Collagen-Induced Arthritis , 2015, PloS one.

[31]  J. Pillow,et al.  Interleukin-1 Receptor Antagonist Protects against Lipopolysaccharide Induced Diaphragm Weakness in Preterm Lambs , 2015, PloS one.

[32]  D. McAuley,et al.  Stem cells for respiratory failure , 2015, Current opinion in critical care.

[33]  D. Prough,et al.  Human mesenchymal stem cells reduce the severity of acute lung injury in a sheep model of bacterial pneumonia , 2014, Thorax.

[34]  J. Tedrow,et al.  Human adult bone marrow-derived stem cells decrease severity of lipopolysaccharide-induced acute respiratory distress syndrome in sheep , 2014, Stem Cell Research & Therapy.

[35]  M. Hoogduijn,et al.  Morphology and size of stem cells from mouse and whale: observational study , 2013, BMJ.

[36]  R. Hubrecht.  Revised Australian Code for the care and use of animals for scientific purposes , 2013, Animal Welfare.

[37]  T. Okano,et al.  Tissue factor triggers procoagulation in transplanted mesenchymal stem cells leading to thromboembolism. , 2013, Biochemical and biophysical research communications.

[38]  J. Laffey,et al.  Mesenchymal stem cells enhance recovery and repair following ventilator-induced lung injury in the rat , 2011, Thorax.

[39]  Arthur S Slutsky,et al.  An official American Thoracic Society workshop report: features and measurements of experimental acute lung injury in animals. , 2011, American journal of respiratory cell and molecular biology.

[40]  M. Matthay,et al.  Antibacterial Effect of Human Mesenchymal Stem Cells Is Mediated in Part from Secretion of the Antimicrobial Peptide LL‐37 , 2010, Stem cells.

[41]  Jae W. Lee,et al.  Allogeneic Human Mesenchymal Stem Cells Restore Epithelial Protein Permeability in Cultured Human Alveolar Type II Cells by Secretion of Angiopoietin-1*♦ , 2010, The Journal of Biological Chemistry.

[42]  C. Herndon,et al.  Differential Expression of Interleukin-8 by Polymorphonuclear Leukocytes of Two Closely Related Species, Ovis canadensis and Ovis aries, in Response to Mannheimia haemolytica Infection , 2010, Infection and Immunity.

[43]  M. Pittenger,et al.  Multilineage potential of adult human mesenchymal stem cells. , 1999, Science.

[44]  W. Hare,et al.  The broncho-pulmonary segments in the sheep. , 1955, Journal of anatomy.

[45]  Kristin M. Reddoch,et al.  Procoagulant activity of human mesenchymal stem cells , 2017 .

[46]  J. Laffey,et al.  Translational Research in Acute Lung Injury and Pulmonary Fibrosis Clinical grade allogeneic human mesenchymal stem cells restore alveolar fluid clearance in human lungs rejected for transplantation , 2014 .

[47]  I. Cuthill,et al.  Reporting : The ARRIVE Guidelines for Reporting Animal Research , 2010 .

[48]  D. Prockop,et al.  Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. , 2006, Cytotherapy.