Alasdair G. Kay
THERAPEUTIC EFFECTS OF HYPOXIC AND PRO-INFLAMMATORY PRIMING OF MESENCHYMAL STEM CELL-DERIVED EXTRACELLULAR VESICLES IN INFLAMMATORY ARTHRITIS
Kay, Alasdair G.; Treadwell, Kane; Roach, Paul; Morgan, Rebecca; Lodge, Rhys; Hyland, Mairead; Piccinini, Anna M.; Forsyth, Nicholas R.; Kehoe, Oksana
Authors
Kane Treadwell
Paul Roach
Rebecca Morgan
Rhys Lodge
Mairead Hyland
Anna M. Piccinini
Nicholas R. Forsyth
Oksana Kehoe o.kehoe@keele.ac.uk
Abstract
<jats:title>Abstract</jats:title><jats:p>Novel biological therapies have revolutionised the management of Rheumatoid Arthritis (RA) but no cure currently exists. Mesenchymal stem cells (MSCs) immunomodulate inflammatory responses through paracrine signalling, including via secretion of extracellular vesicles (EVs) in the cell secretome. We evaluated the therapeutic potential of MSCs-derived small EVs in an antigen-induced model of arthritis (AIA).</jats:p><jats:p>EVs isolated from MSCs cultured normoxically (21% O<jats:sub>2</jats:sub>, 5% CO<jats:sub>2</jats:sub>), hypoxically (2% O<jats:sub>2</jats:sub>, 5% CO<jats:sub>2</jats:sub>) or with a pro-inflammatory cytokine cocktail were applied into the AIA model. Disease pathology was assessed post-arthritis induction through swelling and histopathological analysis of synovial joint structure. Activated CD4+ T cells from healthy mice were cultured with EVs or MSCs to assess deactivation capabilities prior to application of standard EVs <jats:italic>in vivo</jats:italic> to assess T cell polarisation within the immune response to AIA.</jats:p><jats:p>All EVs treatments reduced knee-joint swelling whilst only normoxic and pro-inflammatory primed EVs improved histopathological outcomes. In vitro culture with EVs did not achieve T cell deactivation. Polarisation towards CD4+ helper cells expressing IL17a (Th17) was reduced when normoxic and hypoxic EV treatments were applied in vitro. Normoxic EVs applied into the AIA model reduced Th17 polarisation and improved Th17:Treg homeostatic balance.</jats:p><jats:p>Priming of MSCs in EV production can be applied to alter the therapeutic efficacy however normoxic EVs present the optimal strategy for broad therapeutic benefit. The varied outcomes observed in MSCs priming may promote EVs optimised for therapies targeted for specific therapeutic priorities. EVs present an effective novel technology with potential for cell-free therapeutic translation.</jats:p>
Journal Article Type | Article |
---|---|
Acceptance Date | Dec 20, 2021 |
Online Publication Date | Dec 23, 2021 |
Publicly Available Date | Mar 28, 2024 |
Journal | International Journal of Molecular Sciences |
Print ISSN | 1661-6596 |
Electronic ISSN | 1422-0067 |
Publisher | MDPI |
Peer Reviewed | Peer Reviewed |
Volume | 23 |
Issue | 1 |
Article Number | 126 |
DOI | https://doi.org/10.3390/ijms23010126 |
Related Public URLs | https://www.biorxiv.org/content/10.1101/2021.06.28.450178v2 |
Files
2021.06.28.450178v2.full (1).pdf
(1.7 Mb)
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Publisher Licence URL
https://creativecommons.org/licenses/by-nc/4.0/
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