DEVELOPMENT OF IN VITRO MODEL SYSTEMS OF ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS) TO EVALUATE MESENCHYMAL STROMAL CELL THERAPIES

• Published in: Cytotherapy (Oxford, England) England), 2024-06, Vol.26 (6), p.S49-S50
• Main Authors: Jimenez, A.C., Frey, N., Roy, K.
• Format: Article
• Language: English
• Subjects: acute respiratory distress syndrome; manufacturing parameters; Mesenchymal Stromal Cell
• ISSN: 1465-3249; 1477-2566
• DOI: 10.1016/j.jcyt.2024.03.085

Acute respiratory distress syndrome (ARDS) affects between 10-15% of patients in intensive care units. This life threating condition is often caused by injury or infection resulting in fluid buildup in the lungs causing reduced oxygen flow in the bloodstream, poor oxygenation of organs, impaired function and a high mortality rate. There remains an unmet clinical need for new treatments to improve patient outcomes in ARDS. Mesenchymal stromal cells (MSCs) could serve as a potential therapy of ARDS due to their anti-inflammatory and tissue reparative capabilities. MSC-based therapies have had widely varying results in clinical trials for various diseases, and their effectiveness and mechanism of action are poorly understood, especially for ARDS. The objective of this work was to develop a series of human-mouse hybrid microphysiological models, to assess MSC therapeutic potential in ARDS by understanding MSC and immune cell interactions influenced by manufacturing parameters. We assessed 7 unique MSC donors from bone marrow or umbilical cord tissue. All donors were expanded using xeno-free media with various manufacturing process parameters considered to create 28 different MSC batches. Optimization of the in vitro system was performed to ensure reproducibility of the in vitro microphysiological models before incorporating MSCs as a therapeutic(Fig 1). The model was assessed in immune competent systems containing THP-1s, THP-1 with peripheral blood mononuclear cells, and human whole blood excluding red blood cells. With MSCs administered as a therapeutic intervention, 4 quantitative outputs were assessed. A permeability assay show MSCs can significantly improve LPS induced damage on the transwell membrane through secreted factors. With flow cytometry, changes in macrophage polarization occurs and the expression of HLA-DR on various immune cells is altered in the presence of MSCs. Cytokine responses show high levels of inflammatory cytokines in the absence of MSCs, but once present, high levels of growth factors and production of chemokines including IP-10 and MCP-1 are produced indicating MSCs are mediating inflammation and promoting tissue repair(Fig 2). In this work we successfully developed a human-mouse hybrid ARDS in vitro system to assess MSC responses. We also observed the role MSC process parameters can have on therapeutic potential and shed light on defining critical parameters to refine cell therapy manufacturing and improve their clinical outcomes.