Tunstead, Courteney and Volkova, Evelina and Dunbar, Hazel and Hawthorne, Ian J. and Bell, Alison and Crowe, Louise and Masterson, Joanne C. and Dos Santos, Claudia C. and McNicholas, Bairbre and Laffey, John G. and English, Karen (2024) The ARDS microenvironment enhances MSC-induced repair via VEGF in experimental acute lung inflammation. Molecular Therapy, 32 (10). pp. 3422-3432. ISSN 1525-0016

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Abstract

Clinical trials investigating the potential of mesenchymal stromal cells (MSCs) for the treatment of inflammatory diseases, such as acute respiratory distress syndrome (ARDS), have been disappointing, with less than 50% of patients responding to treatment. Licensed MSCs show enhanced therapeutic efficacy in response to cytokine-mediated activation signals. There are two distinct sub-phenotypes of ARDS: hypo- and hyper-inflammatory. We hypothesized that pre-licensing MSCs in a hyper-inflammatory ARDS environment would enhance their therapeutic efficacy in acute lung inflammation (ALI). Serum samples from patients with ARDS were segregated into hypoand hyper-inflammatory categories based on interleukin (IL)-6 levels. MSCs were licensed with pooled serum from patients with hypo- or hyper-inflammatory ARDS or healthy serum controls. Our findings show that hyper-inflammatory ARDS pre-licensed MSC conditioned medium (MSCCMHyper) led to a significant enrichment in tight junction expression and enhanced barrier integrity in lung epithelial cells in vitro and in vivo in a vascular endothelial growth factor (VEGF)-dependent manner. Importantly, while both MSC-CMHypo and MSC-CMHyper significantly reduced IL-6 and tumor necrosis factor alpha (TNF-a) levels in the bronchoalveolar lavage fluid (BALF) of lipopolysaccharide (LPS)-induced ALI mice, only MSC-CMHyper significantly reduced lung permeability and overall clinical outcomes including weight loss and clinical score. Thus, the hypo- and hyper-inflammatory ARDS environments may differentially influence MSC cytoprotective and immunomodulatory functions.

Item Type:	Article
Keywords:	MSC; ARDS SARS-CoV-2; VEGF; permeability;
Academic Unit:	Faculty of Science and Engineering > Biology
Item ID:	19173
Identification Number:	https://doi.org/10.1016/j.ymthe.2024.08.003
Depositing User:	Karen English
Date Deposited:	11 Nov 2024 16:59
Journal or Publication Title:	Molecular Therapy
Publisher:	Elsevier
Refereed:	Yes
URI:	Publisher
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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