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.
Bibliographical noteFunding Information:
European Respiratory Society (ERS) for financial support.
A.A is supported by R01HL122372 (NIH/NHLBI), ASHARE15A0 (CFF), and the Translational Research Core (STANTO19R0 to BAS and P30DK117469 to Dean Madden). T.H.H and B.A.S are supported by grants from the NIH (P30-DK117469 and R01 HL151385) and the Cystic Fibrosis Foundation (STANTO19R0, STANTO19GO and STANTO02PO). S.R.E is supported by a Marie Curie Postdoctoral Research Fellowship (RESPIRE3) from the European Respiratory Society and the European Union’s H2020 research and innovation programme (Marie Sklodowska-Curie grant agreement No. 713406). D.J.W is supported by the National Heart Lung Blood Institute (HL127144, EB024329), Department of Defense, Cystic Fibrosis Foundation, and the University of Vermont. D.H.M MSC manufacturing was funded through the NIH Production Assistance for Cellular Therapies (PACT) contract with the University of Minnesota, Molecular and Cellular Therapeutics (HHSN268201600014I; PI: DHM). K.E is supported by an Irish Reserch Council Laureate award IRCLA/2017/288. A.K is supported by UK Medical Research Council Research Awards (MRC MR/R025096/1 and MR/S009426/1). P.R.M.R is supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico e Fundação Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro. M.A.M is supported by HL134828 and HL140026.
grants from the NIH and NSF and is supported by a Cancer Centre Core Grant (P30CA023108)
© 2021 European Respiratory Society. All rights reserved.
- Acute Respiratory Distress Syndrome
- Bronchoalveolar Lavage Fluid
- Cell Therapy
- Mesenchymal Stromal Cells
- Respiratory Distress Syndrome
- Mesenchymal Stem Cell Transplantation
- Mesenchymal Stem Cells
PubMed: MeSH publication types
- Research Support, Non-U.S. Gov't
- Research Support, U.S. Gov't, Non-P.H.S.
- Journal Article
- Research Support, N.I.H., Extramural