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

Abstract

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). EVs isolated from MSCs cultured normoxically (21% O2, 5% CO2 ), hypoxically (2% O2, 5% CO2 ) 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 in vivo to assess T cell polarisation within the immune response to AIA. 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 Regulatory T cell (Treg):Th17 homeostatic balance. Normoxic EVs present the optimal strategy for broad therapeutic benefit. EVs present an effective novel technology with the potential for cell-free therapeutic translation.

Citation

Kay, A. G., Treadwell, K., Roach, P., Morgan, R., Lodge, R., Hyland, M., …Kehoe, O. (2022). Therapeutic Effects of Hypoxic and Pro-Inflammatory Priming of Mesenchymal Stem Cell-Derived Extracellular Vesicles in Inflammatory Arthritis. International Journal of Molecular Sciences, 23(1), Article 126. https://doi.org/10.3390/ijms23010126

• Journal Article Type: Article
• Acceptance Date: Dec 20, 2021
• Online Publication Date: Dec 23, 2021
• Publication Date: Jan 1, 2022
• Deposit Date: Jan 4, 2022
• Publicly Available Date: Jan 6, 2022
• Journal: International Journal of Molecular Sciences
• Print ISSN: 1661-6596
• Electronic ISSN: 1422-0067
• Publisher: MDPI AG
• Peer Reviewed: Peer Reviewed
• Volume: 23
• Issue: 1
• Article Number: 126
• DOI: https://doi.org/10.3390/ijms23010126
• Keywords: Inorganic Chemistry; Organic Chemistry; Physical and Theoretical Chemistry; Computer Science Applications; Spectroscopy; Molecular Biology; General Medicine; Catalysis
• Public URL: https://nottingham-repository.worktribe.com/output/7108893
• Publisher URL: https://www.mdpi.com/1422-0067/23/1/126