Sara Rolandsson Enes1,2, Thomas H Hampton3, Jayita Barua1, David H McKenna4, Claudia C Dos Santos5, Eyal Amiel6, Alix Ashare3,7, Kathleen D Liu8, Anna D Krasnodembskaya9, Karen English10, Bruce A Stanton3, Patricia R M Rocco11,12, Michael A Matthay8, Daniel J Weiss13. 1. Dept of Medicine, Larner College of Medicine, University of Vermont, Burlington, VT, USA. 2. Dept of Experimental Medical Science, Lung Biology Unit, Lund University, Lund, Sweden. 3. Dept of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA. 4. Dept of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA. 5. Interdepartmental Division of Critical Care, Dept of Medicine and the Keenan Center for Biomedical Research, St. Michael's Hospital, University of Toronto, Toronto, ON, Canada. 6. Dept of Biomedical and Health Sciences, College of Nursing and Health Sciences, University of Vermont, Burlington, VT, USA. 7. Section of Pulmonary and Critical Care Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA. 8. Depts of Medicine and Anesthesiology and the Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA. 9. Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry, and Biomedical Sciences, Queens University, Belfast, UK. 10. Cellular Immunology Laboratory, Biology Dept, Kathleen Lonsdale Institute for Human Health Research, Maynooth University, Maynooth, Ireland. 11. Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. 12. National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, Brazil. 13. Dept of Medicine, Larner College of Medicine, University of Vermont, Burlington, VT, USA daniel.weiss@med.uvm.edu.
Abstract
BACKGROUND: Despite increased interest in mesenchymal stromal cell (MSC)-based cell therapies for acute respiratory distress syndrome (ARDS), clinical investigations have not yet been successful and our understanding of the potential in vivo mechanisms of MSC actions in ARDS remains limited. ARDS is driven by an acute severe innate immune dysregulation, often characterised by inflammation, coagulation and cell injury. How this inflammatory microenvironment influences MSC functions remains to be determined. AIM: The aim of this study was to comparatively assess how the inflammatory environment present in ARDS lungs versus the lung environment present in healthy volunteers alters MSC behaviour. METHODS: Clinical-grade human bone marrow-derived MSCs (hMSCs) were exposed to bronchoalveolar lavage fluid (BALF) samples obtained from ARDS patients or from healthy volunteers. Following exposure, hMSCs and their conditioned media were evaluated for a broad panel of relevant properties, including viability, levels of expression of inflammatory cytokines, gene expression, cell surface human leukocyte antigen expression, and activation of coagulation and complement pathways. RESULTS: Pro-inflammatory, pro-coagulant and major histocompatibility complex (self-recognition) related gene expression was markedly upregulated in hMSCs exposed ex vivo to BALF obtained from healthy volunteers. These changes were less apparent and often opposite in hMSCs exposed to ARDS BALF samples. CONCLUSION: These data provide new insights into how hMSCs behave in healthy versus inflamed lung environments, and strongly suggest that the inflamed environment in ARDS induces hMSC responses that are potentially beneficial for cell survival and actions. This further highlights the need to understand how different disease environments affect hMSC functions.
BACKGROUND: Despite increased interest in mesenchymal stromal cell (MSC)-based cell therapies for acute respiratory distress syndrome (ARDS), clinical investigations have not yet been successful and our understanding of the potential in vivo mechanisms of MSC actions in ARDS remains limited. ARDS is driven by an acute severe innate immune dysregulation, often characterised by inflammation, coagulation and cell injury. How this inflammatory microenvironment influences MSC functions remains to be determined. AIM: The aim of this study was to comparatively assess how the inflammatory environment present in ARDS lungs versus the lung environment present in healthy volunteers alters MSC behaviour. METHODS: Clinical-grade human bone marrow-derived MSCs (hMSCs) were exposed to bronchoalveolar lavage fluid (BALF) samples obtained from ARDS patients or from healthy volunteers. Following exposure, hMSCs and their conditioned media were evaluated for a broad panel of relevant properties, including viability, levels of expression of inflammatory cytokines, gene expression, cell surface human leukocyte antigen expression, and activation of coagulation and complement pathways. RESULTS: Pro-inflammatory, pro-coagulant and major histocompatibility complex (self-recognition) related gene expression was markedly upregulated in hMSCs exposed ex vivo to BALF obtained from healthy volunteers. These changes were less apparent and often opposite in hMSCs exposed to ARDS BALF samples. CONCLUSION: These data provide new insights into how hMSCs behave in healthy versus inflamed lung environments, and strongly suggest that the inflamed environment in ARDS induces hMSC responses that are potentially beneficial for cell survival and actions. This further highlights the need to understand how different disease environments affect hMSC functions.
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